U.S. patent application number 14/324948 was filed with the patent office on 2014-10-30 for steroid-containing sustained release intraocular implants and related methods.
The applicant listed for this patent is ALLERGAN, INC.. Invention is credited to Wendy M. Blanda, James N. Chang, Glenn T. Huang, Thierry Nivaggioli, Orest Olejnik, Lon T. Spada, Hiroshi Sugimoto.
Application Number | 20140322295 14/324948 |
Document ID | / |
Family ID | 38695513 |
Filed Date | 2014-10-30 |
United States Patent
Application |
20140322295 |
Kind Code |
A1 |
Huang; Glenn T. ; et
al. |
October 30, 2014 |
STEROID-CONTAINING SUSTAINED RELEASE INTRAOCULAR IMPLANTS AND
RELATED METHODS
Abstract
Biocompatible intraocular implants include a steroid and an
auxiliary agent, where the auxiliary agent is present in an amount
sufficient to lessen the severity of at least one side effect
compared to the use of an otherwise identical implant lacking said
auxiliary agent. The steroid and the auxiliary agent may be present
on the same intraocular implant or on different implants. The
steroid and auxiliary agent may be associated with a biodegradable
polymer matrix, such as a matrix of a two biodegradable polymers.
Or, the steroid may be associated with a polymeric coating having
one or more openings effective to permit the steroid to be released
into an external environment. The implants containing the steroid
and an auxiliary agent may be placed in an eye to treat one or more
ocular conditions while reducing the side effects otherwise
accompanying steroid use.
Inventors: |
Huang; Glenn T.; (Fremont,
CA) ; Nivaggioli; Thierry; (Atherton, CA) ;
Spada; Lon T.; (Walnut, CA) ; Sugimoto; Hiroshi;
(Osaka, JP) ; Blanda; Wendy M.; (Tustin, CA)
; Chang; James N.; (Newport Beach, CA) ; Olejnik;
Orest; (Coto de Caza, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALLERGAN, INC. |
Irvine |
CA |
US |
|
|
Family ID: |
38695513 |
Appl. No.: |
14/324948 |
Filed: |
July 7, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13356934 |
Jan 24, 2012 |
8771722 |
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14324948 |
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11932373 |
Oct 31, 2007 |
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13356934 |
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11474149 |
Jun 23, 2006 |
8147865 |
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11932373 |
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11118288 |
Apr 29, 2005 |
8257730 |
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11474149 |
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10837356 |
Apr 30, 2004 |
8119154 |
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11118288 |
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Current U.S.
Class: |
424/428 ;
514/171 |
Current CPC
Class: |
A61K 9/0024 20130101;
A61K 47/593 20170801; A61K 31/58 20130101; A61L 2300/45 20130101;
A61K 9/0092 20130101; A61K 9/204 20130101; A61K 31/573 20130101;
A61L 2300/604 20130101; A61K 31/56 20130101; A61F 9/0017 20130101;
A61L 27/58 20130101; A61L 27/18 20130101; A61L 27/18 20130101; A61L
31/148 20130101; A61L 31/16 20130101; A61K 31/5377 20130101; A61L
2430/16 20130101; A61P 27/02 20180101; A61P 25/00 20180101; A61L
27/54 20130101; A61K 9/0051 20130101; A61L 31/06 20130101; A61L
2300/436 20130101; C08L 67/04 20130101; A61K 2300/00 20130101; A61L
2300/222 20130101; A61K 31/573 20130101; A61P 29/00 20180101; A61K
9/1647 20130101; A61P 27/06 20180101; A61K 45/06 20130101 |
Class at
Publication: |
424/428 ;
514/171 |
International
Class: |
A61L 31/06 20060101
A61L031/06; A61L 31/16 20060101 A61L031/16; A61L 31/14 20060101
A61L031/14 |
Claims
1. A biodegradable intraocular implant, comprising: a steroid; and
an auxiliary agent, wherein the steroid and the auxiliary agent are
associated with a biodegradable polymer in the form of an
intraocular implant.
2. The implant of claim 1, wherein the steroid is selected from the
group consisting of dexamethasone, fluocinolone, fluocinolone
acetonide, triamcinolone, triamcinolone acetonide, salts thereof,
and mixtures thereof
3. The implant of claim 1, wherein the biodegradable polymer is a
poly(lactide-co-glycolide) polymer.
4. The implant of claim 1, wherein the auxiliary agent is selected
from the group consisting of a parasympathomimetic, a
sympathomimetic, an alpha agonist, a beta blocker, a carbonic
anhydrase inhibitor, a prostaglandin analog, a neuroprotectant, and
mixtures thereof.
5. The implant of claim 1, wherein the auxiliary agent is selected
from the group consisting of pilocarpone, carbachol, echothiophate,
epinephrine, dipivefrin, apracionidine, brimonidine, clonidine,
apraclonidine, p-aminoclonidine, oxymetazoline, epinephrine,
norepinephrine, and cirazoline, dexmedatomidine, mivazerol,
xylazine, medatomidine, memantime, timolol, levobunolol,
metipranilol, carteolol, betaxolol, dorzolamine, brinzolamide,
dichlorphenamide, latanoprost, bimatoprost, travaprost,
unoprostone, and mixtures thereof.
6. The implant of claim 1, wherein the implant comprises a
polymeric outer layer which is impermeable to an intraocular
fluid.
7. The implant of claim 6, wherein the outer layer comprises a
plurality of openings or holes in the polymeric outer layer.
8. A biodegradable intraocular implant system, comprising: a
steroid associated with a biodegradable polymer in the form of a
first intraocular implant; and an auxiliary agent associated with a
biodegradable polymer in the form of a second intraocular
implant.
9. A biodegradable intraocular implant system, comprising: a
steroid associated with a biodegradable polymeric component in the
form of an intraocular implant structured for intravitreal
placement in an eye of an individual, the steroid being present in
an amount effective in treating an ocular condition of the eye with
a reduced toxicity relative to intravitreal injection of a liquid
composition containing the same steroid; and an auxiliary agent
associated with a biodegradable polymeric component in the form of
an intraocular implant structured for intravitreal placement in an
eye of an individual, the auxiliary agent being present in an
amount effective to reduce the occurrence of at least one side
effect present upon otherwise identical administration of the
steroid alone.
10. The implant system of claim 9, wherein the steroid is selected
from the group consisting of dexamethasone, fluocinolone,
fluocinolone acetonide, triamcinolone, triamcinolone acetonide,
salts thereof, and mixtures thereof
11. The implant system of claim 9, wherein the auxiliary agent
comprises an antiglaucoma drug is selected from the group
consisting of a parasympathomimetic, a sympathomimetic, an alpha
agonist, a beta blocker, a carbonic anhydrase inhibitor, a
prostaglandin analog, a neuroprotectant, and mixtures thereof.
12. The implant system of claim 9, wherein the implant comprises
steroid and auxiliary agent in alternating layers.
13. The implant system of claim 9, wherein the steroid and the
auxiliary agent are comprised in the same implant.
14. The implant system of claim 9, wherein the steroid and the
auxiliary agent are comprised in different implants.
Description
CROSS REFERENCE
[0001] This application is a continuation of copending U.S.
application Ser. No. 13/356,934, filed Jan. 24, 2012, and herein
incorporated by reference, which is a divisional of U.S.
application Ser. No. 11/932,373, filed Oct. 31, 2007, and hereby
incorporated by reference, which is a continuation of U.S.
application Ser. No. 11/474,149, filed Jun. 23, 2006, and hereby
incorporated by reference, which is a continuation-in-part of U.S.
application Ser. No. 11/118,288, filed Apr. 29, 2005, and hereby
incorporated by reference, which is a continuation-in-part of U.S.
application Ser. No. 10/837,356, filed Apr. 30, 2004, and hereby
incorporated by reference.
BACKGROUND
[0002] The present invention generally relates to devices and
methods to treat an eye of a patient, and more specifically to
intraocular implants that provide extended release of a therapeutic
agent to an eye in which the implant is placed.
[0003] Steroids, such as the corticosteroid, fluocinolone acetonide
(1,4-pregnadien-6.alpha., 9.alpha.-difluoro-11.beta.,
16.alpha.,17,21-tetrol-3,20-dione 16,17-acetonide), are usually
given topically, systemically, or periocularly, as an injection, to
treat uveitis. All three methods of delivery have drawbacks, e.g.,
topical corticosteroids do not treat diseases in the back on the
eye, systemic corticosteroids are often associated with many
unwanted side effects, and periocular injections may sometimes
cause globe perforation, periocular fibrosis and ptosis.
[0004] An alternative that may circumvent the drawbacks of the
above-mentioned delivery methods is to use sustained-released drug
delivery systems. In 2000, Jaffe et al. reported using compressed
pure fluocinolone acetonide pellets coated with silicone and
polyvinyl alcohol as a fluocinolone sustained delivery device
(Jaffe, G. J. et al., Journal of Ophthalmology and Vision Surgery,
Vol 41, No. 11, October 2000). They obtained release rates of
1.9.+-.0.25 4/day (6 months) and 2.2.+-.0.6 .mu.g/day (45 days) for
the 2-mg device and 15-mg device, respectively. The duration of
release for the 2-mg and 15-mg device was estimated to be 2.7 and
18.6 years, respectively. U.S. Pat. Nos. 6,217,895 and 6,548,078
disclose sustained release implants for delivering a
corticosteroid, such as fluocinolone acetonide, to an eye. However,
fluocinolone acetonide intravitreal implants made by Control
Delivery Systems (the assignee of U.S. Pat. Nos. 6,217,895 and
6,548,078) were only partially successful and led to the
development of cataracts and increased intraocular pressure.
[0005] In addition, intravitreal injection of triamcinolone
acetonide (KENALOG.RTM.) for treatments of non-infectious uveitis,
and macular edema due to various retinal diseases has appeared to
be safe and effective.
[0006] Additional biocompatible implants for placement in the eye
have been disclosed in a number of patents, such as U.S. Pat. Nos.
4,521,210; 4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,501,856;
5,766,242; 5,824,072; 5,869,079; 6,074,661; 6,331,313; 6,369,116;
6,699,493, and 6,726,918.
[0007] Other intravitreal therapeutic approaches are described in
U.S. application Ser. No. 10/966,764, filed Oct. 14, 2004; Ser. No.
11/039,192, filed Jan. 19, 2005; and 60/587,092, filed Jul. 12,
2004.
[0008] It would be advantageous to provide eye implantable drug
delivery systems, such as intraocular implants, and methods of
using such systems, that are capable of releasing a therapeutic
agent at a sustained or controlled rate for extended periods of
time and in amounts with few or no negative side effects.
SUMMARY
[0009] The present invention provides new drug delivery systems,
and methods of using such systems, for extended or sustained drug
release into an eye, for example, to achieve one or more desired
therapeutic effects while minimizing an increase in ocular pressure
in the eye. The drug delivery systems are in the form of implants
or implant elements that may be placed in an eye.
[0010] Intraocular implants in accordance with the disclosure
herein comprise a steroid and a antiglaucoma drug. The steroid and
the antiglaucoma drug may be present in or on the same implant or
different implants. The antiglaucoma drug may maintain the ocular
pressure in the eye in an acceptable range.
[0011] Such intraocular implants may comprise a therapeutic
component and a drug release sustaining component associated with
the therapeutic component. In accordance with the present
invention, the therapeutic component comprises, consists
essentially of, or consists of, a steroid. The drug release
sustaining component is associated with the therapeutic component
to sustain release of a therapeutically effective amount of the
steroid into an eye in which the implant is placed. The
therapeutically effective amount of the steroid is preferably
released into the eye for a period of time greater than about two
months after the implant is placed in the eye.
[0012] In one embodiment, the intraocular implants comprise a
steroid and a biodegradable polymer matrix. The steroid is
associated with a biodegradable polymer matrix that releases drug,
such as by degrading, at a rate effective to sustain release of a
therapeutically effective amount of the steroid from the implant
for a time greater or longer than about two months from a time the
implant is placed in an ocular site or region of an eye. The
intraocular implant is biodegradable or bioerodible and provides a
sustained release of the steroid in an eye for extended periods of
time, such as for more than two months, for example for about three
months or more and up to about six months or more.
[0013] The biodegradable polymer component of the foregoing
implants may be a mixture of biodegradable polymers, wherein at
least one of the biodegradable polymers is a polylactic acid or
poly(lactide-co-glycolide) polymer having a molecular weight less
than 40 kiloDaltons (kD). Additionally or alternatively, the
foregoing implants may comprise a first biodegradable polymer
having terminal free acid groups, and a different second
biodegradable polymer having terminal free acid groups.
Furthermore, the foregoing implants may comprise a mixture of
different biodegradable polymers, each biodegradable polymer having
an inherent viscosity in a range of about 0.16 deciliters/gram
(dl/g) to about 0.24 dl/g. Examples of suitable biodegradable
polymers include polymers of lactic acid, glycolic acid, and
mixtures thereof.
[0014] In another embodiment, intraocular implants comprise a
therapeutic component that comprises a steroid, and a polymeric
outer layer covering the therapeutic component. The polymeric outer
layer may include one or more orifices or openings or holes that
are effective to allow a liquid to pass into the implant, and to
allow the steroid to pass out of the implant. The therapeutic
component is provided in a core or interior portion of the implant,
and the polymeric outer layer covers or coats the core. The
polymeric outer layer may include one or more biodegradable
portions. The implant can provide an extended release of the
steroid for more or longer than about two months, and for more than
about one year, and even for more than about five or about ten
years.
[0015] In one embodiment, the polymeric outer layer of the implant
may comprise two or more layers or coats of biodegradable material,
with each such layer having a different composition or rate of
degradation than the layer immediately adjoining it. For example,
the polymeric outer layer of the implant may comprise concentric
rings or nested coatings comprising a first layer, wherein the
first layer may comprise, for example, a biodegradable polymer and
the absence of a steroid, a biodegradable polymer comprising a
therapeutically effective amount of a steroid, a biodegradable
polymer comprising an amount of an auxiliary agent effective to
reduce at least one side effect of a steroid, and a biodegradable
polymer comprising a therapeutically effective amount of a steroid
and an amount of an auxiliary agent effective to reduce at least
one side effect of a steroid, and a biodegradable polymer without
any added drug.
[0016] A second layer may also comprise, for example, a
biodegradable polymer and the absence of a steroid, a biodegradable
polymer comprising a therapeutically effective amount of a steroid,
a biodegradable polymer comprising an amount of an auxiliary agent
able to reduce at least one side effect of a steroid, and a
biodegradable polymer comprising a therapeutically effective amount
of a steroid and an amount of an auxiliary agent able to reduce at
least one side effect of a steroid, and a biodegradable polymer
without any added drug, with the additional provisos that the first
and second layers are located adjoining one another in the
bidegradable implant, that the first and second layers are not
identical, and that the first layer is designed to erode
substantially before the second layer.
[0017] Additional layers may be present; preferably, each such
layer will not be identical to the layers immediately surrounding
it.
[0018] It is well known that long-term ophthalmic treatment with
corticosteroids must be monitored closely due to potential toxicity
and long-term side effects. For example, adverse reactions listed
for conventional ophthalmic dexamethasone preparations include:
glaucoma (with optic nerve damage, visual acuity and field defects,
and ocular hypertension), posterior subcapsular cataract formation,
and secondary ocular infection from pathogens including herpes
simplex. Additional hazardous side-effects upon conventional
topical treatment with steroids may comprise hypertension,
hyperglycemia, increased susceptibility to infection, and peptic
ulcers.
[0019] An "auxiliary agent" is an agent able to reduce at least one
side effect of a steroid. An auxiliary agent comprises a compound
able, in the absence of the steroid, to reduce or prevent a
condition associated with at least one side effect of a steroid.
Thus such a compound may include, for example, one or more
neuroprotective agent such as, without limitation, memantine (and
other NMDA receptor antagonists), brimonidine (and other alpha 2
adrenergic receptor agonists) can be therapeutically useful in the
treatment of optic nerve and retinal damage affecting loss of
visual acuity and diminution of visual field; and/or one or more
ocular hypotensive agent such as, without limitation, beta blockers
(such as timolol), a carbonic anhydrase inhibitor, an alpha 2
adrenergic agonist (such as clonidine, brimonidine and selective
alpha 2B and/or 2C receptor agonists), and a prostaglandin or
prostaglandin derivative or analog (such as bimatoprost,
travoprost, and latanoprost) for the treatment of ocular
hypertension; and/or one or more antiviral and antibiotic drug (for
example, a quinolone antibiotic such as ofloxacin, ciprofloxacin
and norfloxacin) for the prevention of secondary ocular
infection.
[0020] In another embodiment, the implant may include a therapeutic
agent such as a steroid, and an agent able to reduce at least one
side effect of a steroid, wherein art least one of such agents is
covalently joined via a biodegradable linkage to a biodegradable
polymer. For example, the biodegradable polymer may comprise a
plurality of hydroxyl groups to which said agent may be joined by a
biodegradable linkage. Biodegradable or biocleavable linkages are
defined as types of specific chemical moieties or groups that can
be used within the chemical substances that covalently reversibly
couple or cross-link a therapeutic agent and/or an auxiliary agent
to a biodegradable polymer comprised in the implant. Thus, such
linkages may be contained in certain embodiments of the instant
invention that provide the function of controlled release of a
steroid and/or auxiliary agent. In certain embodiments of the
present invention an implant system comprising one or more implant
is structured such that the therapeutic agent and the auxiliary
agent are released at different rates or different times following
implantation of the implant(s). Biocleavable linkages or bonds can
be distinguishable by their structure and function and non-limiting
examples are provided here under distinct categories or types.
[0021] One such category comprises the disulfide linkages that are
well known for covalent coupling. Such linkages are stable under
oxidizing conditions, but can be cleaved under reducing conditions.
For drug delivery, they may be more useful for shorter periods in
vivo since they are cleaved relatively easily. A simple ester bond
is another preferred type that may easily be formed between an acid
and an alcohol. Another preferred type is any imidoester formed
from alkyl imidates. Also included are maleimide bonds as with
sulfhydryls or amines used to incorporate a biocleavable
linkage.
[0022] Another category in this invention comprises acid-cleavable
biocleavable linkages. The preferred biocleavable linkages for such
release of active agents and other moieties. One such type is an
acid-sensitive (or acid-labile) hydrazone linkage as described by
Greenfield, et al, Cancer Res. 50, 6600-6607 (1990), and references
therein.
[0023] Another type of acid-labile linkage are the polyortho or
diortho ester linkage; examples of such linkages are disclosed in
J. Heller, et al., METHODS IN ENZYMOLOGY 112, 422-436 (1985), J.
Heller, J. ADV. POLYMER SCI. 107, 41 (1993), M. Ahmad, et al., J.
AMER. CHEM. SOC. 101, 2669 (1979) and references therein. Also
useful may be acid labile phosphonamide linkages disclosed by J.
Rahil, et al, J. AM. CHEM. SOC. 103, 1723 (1981) and J. H. Jeong,
et al, BIOCONJ. CHEM. 14, 473 (2003).
[0024] The steroid of the implants disclosed herein may be
corticosteroids, or other steroids that are effective in treating
ocular conditions. One example of a suitable steroid is
fluocinolone or fluocinolone acetonide. Another example of a
suitable steroid is triamcinolone or triamcinolone acetonide.
Another example of a suitable steroid is beclomethasone or
beclomethasone dipropionate. Another example of a suitable steroid
is dexamethasone or a pharmacologically acceptable salt thereof. In
addition, the therapeutic component of the present implants may
include one or more additional and different therapeutic agents
that may be effective in treating an ocular condition.
[0025] The implants may be placed in an ocular region to treat a
variety of ocular conditions, including conditions that affect an
anterior region or posterior region of an eye. For example, the
implants may be used to treat many conditions of the eye,
including, without limitation, maculopathies and retinal
degeneration, uveitis, retinitis, choroiditis, vascular diseases,
and exudative diseases, proliferative disorders, infectious
disorders, genetic disorders, tumors, trauma, and surgery, retinal
tears or holes, and the like. In particular, treatment of retinal
conditions are particularly advantageous by means if insertion,
injection or other intravitreal delivery, or subconjunctival
delivery of such implants.
[0026] Kits in accordance with the present invention may comprise
one or more of the present implants, and instructions for using the
implants. For example, the instructions may explain how to
administer the implants to a patient, and types of conditions that
may be treated with the implants.
[0027] Each and every feature described herein, and each and every
combination of two or more of such features, is included within the
scope of the present invention provided that the features included
in such a combination are not mutually inconsistent. In addition,
any feature or combination of features may be specifically excluded
from any embodiment of the present invention.
[0028] Additional aspects and advantages of the present invention
are set forth in the following description and claims, particularly
when considered in conjunction with the accompanying drawings and
examples.
DRAWINGS
[0029] FIG. 1 is a graph showing the cumulative release profiles
for biodegradable fluocinolone acetonide containing implants as
determined in 0.9% saline at 37 degrees Celsius.
[0030] FIG. 2 is a graph similar to FIG. 1 showing the cumulative
release profiles for biodegradable fluocinolone acetonide
containing implants with different combinations of biodegradable
polymers.
[0031] FIG. 3 is a graph similar to FIG. 1 showing the cumulative
release profiles for biodegradable triamcinolone acetonide
containing implants.
[0032] FIG. 4 is a graph showing the cumulative release profiles
for non-sterile fluocinolone acetonide containing implants having
different hole configurations.
[0033] FIG. 5 is a graph showing the amount of fluocinolone
released per day for the implants described in FIG. 4.
[0034] FIG. 6 is a graph showing the cumulative release profiles
for sterile fluocinolone acetonide containing implants having
different hole configurations.
[0035] FIG. 7 is a graph showing the amount of fluocinolone
released per day for the implants described in FIG. 6.
[0036] FIG. 8 is a graph showing the cumulative release profiles
for non-sterile fluocinolone acetonide containing implants having
different hole configurations than those described in FIG. 4.
[0037] FIG. 9 is a graph showing the amount of fluocinolone
released per day for the implants described in FIG. 8.
[0038] FIG. 10 is a graph showing the cumulative release profiles
for sterile fluocinolone acetonide containing implants having hole
configurations similar to those described in FIG. 8.
[0039] FIG. 11 is a graph showing the amount of fluocinolone
released per day for the implants described in FIG. 10.
[0040] FIG. 12 is a graph showing the cumulative release profiles
for sterile fluocinolone acetonide containing implants having
different hole configurations.
[0041] FIG. 13 is a graph showing the amount of fluocinolone
released per day for the implants described in FIG. 12.
[0042] FIG. 14 is a graph showing the cumulative release profiles
for non-sterile fluocinolone acetonide containing implants having
different hole configurations.
[0043] FIG. 15 is a graph showing the amount of fluocinolone
released per day for the implants described in FIG. 14.
[0044] FIG. 16 is a graph showing the cumulative release profiles
for sterile fluocinolone acetonide containing implants described in
FIG. 14.
[0045] FIG. 17 is a graph showing the amount of fluocinolone
released per day for the implants described in FIG. 16.
[0046] FIG. 18 is a graph showing the total percent release of
triamcinalone as a function of time in phosphate buffered saline
for implants containing 30% triamcinalone.
[0047] FIG. 19 is a graph showing the total percent release of
triamcinalone as a function of time in phosphate buffered saline
for implants containing 50% triamcinalone.
[0048] FIG. 20 is a graph showing the total percent release of
triamcinalone as a function of time in citrate phosphate buffer for
implants containing 30% triamcinalone.
[0049] FIG. 21 is a graph showing the total percent release of
triamcinalone as a function of time in citrate phosphate buffer for
implants containing 50% triamcinalone.
[0050] FIG. 22 is a graph showing the total percent release of
beclomethasone propionate as a function of time in phosphate
buffered saline for implants containing 30% triamcinalone.
[0051] FIG. 23 is a graph showing the total percent release of
beclomethasone propionate as a function of time in phosphate
buffered saline for implants containing 50% triamcinalone.
[0052] FIG. 24 is a graph showing the total percent release of
beclomethasone propionate as a function of time in citrate
phosphate buffer for implants containing 30% triamcinalone.
[0053] FIG. 25 is a graph showing the total percent release of
beclomethasone propionate as a function of time in citrate
phosphate buffer for implants containing 50% triamcinalone.
DESCRIPTION
[0054] As described herein, controlled and sustained administration
of a therapeutic agent through the use of one or more intraocular
implants may improve treatment of undesirable ocular conditions.
The implants comprise a pharmaceutically acceptable polymeric
composition and are formulated to release one or more
pharmaceutically active agents including at least one steroid and
optionally at least one auxiliary agent, over an extended period of
time. In certain embodiments involving the delivery of more than
one agent, the dosage regiment may be formulated to provide two or
more drugs to the posterior segment of the eye under different
dosage regimens. For example, the dosage of the steroid in an
implant may be made to be discontinuous over the treatment period
while a non-discontinuous dosage of an auxiliary agent is
administered in an implant over the same overall time period. The
implant containing the steroid and the implant containing the
auxiliary agent may be different implants or the same implant
comprising means of differentially administering the steroid and
auxiliary agent, such means including different coatings or shells
which may contain, neither, one or both drugs (as discussed
elsewhere herein), or covalent linkage of one or both drugs to a
biodegradable polymer of the implant by way of a biodegradable
linkage, thus permitting regulation of the delivery of one or more
drug over the time of the treatment. The implants are effective to
provide a therapeutically effective dosage of the agent or agents
directly to a region of the eye to treat one or more undesirable
ocular conditions. Thus, with a single administration, therapeutic
agents will be made available at the site where they are needed and
may be maintained for an extended period of time, rather than
subjecting the patient to repeated injections or, in the case of
self-administered drops, ineffective treatment with only limited
bursts of exposure to the active agent or agents.
[0055] A preferred intraocular implant in accordance with the
disclosure herein comprises a therapeutic component and a drug
release sustaining component associated with the therapeutic
component. In accordance with the present invention, the
therapeutic component comprises, consists essentially of, or
consists of, a steroid. The drug release sustaining component is
associated with the therapeutic component to sustain release of a
therapeutically effective amount of the steroid into an eye in
which the implant is placed. The therapeutic amount of the steroid
is released into the eye for a period of time greater than about
two months after the implant is placed in the eye. Preferably the
implant also comprises an agent able to reduce at least one side
effect of a steroid (AARSS). For example, in one embodiment
DEFINITIONS
[0056] For the purposes of this description, we use the following
terms as defined in this section, unless the context of the word
indicates a different meaning.
[0057] As used herein, an "intraocular implant" refers to a device
or element that is structured, sized, or otherwise configured to be
placed "in an eye", including the subconjunctival space.
Intraocular implants are generally biocompatible with physiological
conditions of an eye and do not cause adverse side effects.
Intraocular implants may be placed in an eye without disrupting
vision of the eye.
[0058] As used herein, a "therapeutic component" refers to a
portion of an intraocular implant comprising one or more
therapeutic agents or substances used to treat a medical condition
of the eye. The therapeutic component may be a discrete region of
an intraocular implant, or it may be homogenously distributed
throughout the implant. The therapeutic agents of the therapeutic
component are typically ophthalmically acceptable, and are provided
in a form that does not cause adverse reactions when the implant is
placed in an eye.
[0059] As used herein, a "drug release sustaining component" refers
to a portion of the intraocular implant that is effective to
provide a sustained release of the therapeutic agents of the
implant. A drug release sustaining component may be a biodegradable
polymer matrix, or it may be a coating covering a core region of
the implant that comprises a therapeutic component.
[0060] As used herein, "associated with" means mixed with,
dispersed within, coupled to, covering, or surrounding. With
respect to intraocular implants which comprise a therapeutic
component associated with a biodegradable polymer matrix,
"associated with" specifically excludes biodegradable polymeric
coatings that may be provided on or around the matrix.
[0061] As used herein, an "ocular region" or "ocular site" refers
generally to any area of the eyeball, including the anterior and
posterior segment of the eye, and which generally includes, but is
not limited to, any functional (e.g., for vision) or structural
tissues found in the eyeball, or tissues or cellular layers that
partly or completely line the interior or exterior of the eyeball.
Specific examples of areas of the eyeball in an ocular region
include the anterior chamber, the posterior chamber, the vitreous
cavity, the choroid, the suprachoroidal space, the conjunctiva, the
subconjunctival space, the episcleral space, the intracorneal
space, the epicorneal space, the sclera, the pars plana,
surgically-induced avascular regions, the macula, and the
retina.
[0062] As used herein, an "ocular condition" is a disease, ailment
or condition which affects or involves the eye or one of the parts
or regions of the eye. Broadly speaking the eye includes the
eyeball and the tissues and fluids which constitute the eyeball,
the periocular muscles (such as the oblique and rectus muscles) and
the portion of the optic nerve which is within or adjacent to the
eyeball.
[0063] An anterior ocular condition is a disease, ailment or
condition which affects or which involves an anterior (i.e. front
of the eye) ocular region or site, such as a periocular muscle, an
eye lid or an eye ball tissue or fluid which is located anterior to
the posterior wall of the lens capsule or ciliary muscles. Thus, an
anterior ocular condition primarily affects or involves the
conjunctiva, the cornea, the anterior chamber, the iris, the
posterior chamber (behind the retina but in front of the posterior
wall of the lens capsule), the lens or the lens capsule and blood
vessels and nerve which vascularize or innervate an anterior ocular
region or site.
[0064] Thus, an anterior ocular condition can include a disease,
ailment or condition, such as for example, aphakia; pseudophakia;
astigmatism; blepharospasm; cataract; conjunctival diseases;
conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes;
eyelid diseases; lacrimal apparatus diseases; lacrimal duct
obstruction; myopia; presbyopia; pupil disorders; refractive
disorders and strabismus. Glaucoma can also be considered to be an
anterior ocular condition because a clinical goal of glaucoma
treatment can be to reduce a hypertension of aqueous fluid in the
anterior chamber of the eye (i.e. reduce intraocular pressure).
[0065] A posterior ocular condition is a disease, ailment or
condition which primarily affects or involves a posterior ocular
region or site such as choroid or sclera (in a position posterior
to a plane through the posterior wall of the lens capsule),
vitreous, vitreous chamber, retina, optic nerve (i.e. the optic
disc), and blood vessels and nerves which vascularize or innervate
a posterior ocular region or site.
[0066] Thus, a posterior ocular condition can include a disease,
ailment or condition, such as for example, acute macular
neuroretinopathy; Behcet's disease; choroidal neovascularization;
diabetic uveitis; histoplasmosis; infections, such as fungal or
viral-caused infections; macular degeneration, such as acute
macular degeneration, non-exudative age related macular
degeneration and exudative age related macular degeneration; edema,
such as macular edema, cystoid macular edema and diabetic macular
edema; multifocal choroiditis; ocular trauma which affects a
posterior ocular site or location; ocular tumors; retinal
disorders, such as central retinal vein occlusion, diabetic
retinopathy (including proliferative diabetic retinopathy),
proliferative vitreoretinopathy (PVR), retinal arterial occlusive
disease, retinal detachment, uveitic retinal disease; sympathetic
opthalmia; Vogt Koyanagi-Harada (VKH) syndrome; uveal diffusion; a
posterior ocular condition caused by or influenced by an ocular
laser treatment; posterior ocular conditions caused by or
influenced by a photodynamic therapy, photocoagulation, radiation
retinopathy, epiretinal membrane disorders, branch retinal vein
occlusion, anterior ischemic optic neuropathy, non-retinopathy
diabetic retinal dysfunction, retinitis pigmentosa, and glaucoma.
Glaucoma can be considered a posterior ocular condition because the
therapeutic goal is to prevent the loss of or reduce the occurrence
of loss of vision due to damage to or loss of retinal cells or
optic nerve cells (i.e. neuroprotection).
[0067] The term "biodegradable polymer" refers to a polymer or
polymers which degrade in vivo, and wherein erosion of the polymer
or polymers over time occurs concurrently with or subsequent to
release of the therapeutic agent. Specifically, hydrogels such as
methylcellulose which act to release drug through polymer swelling
are specifically excluded from the term "biodegradable polymer".
The terms "biodegradable" and "bioerodible" are equivalent and are
used interchangeably herein. A biodegradable polymer may be a
homopolymer, a copolymer, or a polymer comprising more than two
different polymeric units.
[0068] The term "treat", "treating", or "treatment" as used herein,
refers to reduction or resolution or prevention of an ocular
condition, ocular injury or damage, or to promote healing of
injured or damaged ocular tissue.
[0069] The term "therapeutically effective amount" as used herein,
refers to the level or amount of agent needed to treat an ocular
condition, or reduce or prevent ocular injury or damage without
causing significant negative or adverse side effects to the eye or
a region of the eye.
[0070] Intraocular implants have been developed which can release
drug loads over various time periods. These implants, which when
inserted into an eye, such as, without limitation, the vitreous of
an eye or the subconjunctival space, provide therapeutic levels of
a steroid and/or auxiliary agent for extended periods of time
(e.g., for about 2 months or more). The implants disclosed are
effective in treating ocular conditions, such as posterior ocular
conditions.
[0071] In one embodiment of the present invention, an intraocular
implant comprises a biodegradable polymer matrix. The biodegradable
polymer matrix is one type of a drug release sustaining component.
The biodegradable polymer matrix is effective in forming a
biodegradable intraocular implant. The biodegradable intraocular
implant may comprises a steroid and or auxiliary agent associated
with the biodegradable polymer matrix. Such association may be
"passive", such as through co-extrusion of the active agent(s) with
the biodegradable polymer, or "active", by being joined, or coupled
to the polymer through covalent chemical bonds, chelation, strong
hydrogen bonding, ionic interaction, and the like. The matrix
degrades at a rate effective to sustain release of a
therapeutically effective amount of the steroid for a time greater
than about two months from the time in which the implant is placed
in ocular region or ocular site, such as the vitreous of an
eye.
[0072] The steroid of the implant may be a corticosteroid. In
certain embodiments, the steroid may be a fluocinolone, a
triamcinolone, or a mixture of fluocinolone and triamcinolone. In
some embodiments, the fluocinolone is provided in the implant as
fluocinolone acetonide, and the triamcinolone is provided in the
implant as triamcinolone acetonide. Triamcinolone acetonide is
publicly available under the tradename, KENALOG.RTM.. Another
steroid useful in the present implants is beclomethasone or
beclomethasone diproprionate. Thus, the present implants may
comprise one or more of the following: fluocinolone, fluocinolone
acetonide, triamcinolone, triamcinolone acetonide, beclomethasone,
or beclamethasone diproprionate.
[0073] The steroid may be in a particulate or powder form and
entrapped by the biodegradable polymer matrix. Usually, steroid
particles will have an effective average size less than about 3000
nanometers. In certain implants, the particles may have an
effective average particle size about an order of magnitude smaller
than 3000 nanometers. For example, the particles may have an
effective average particle size of less than about 500 nanometers.
In additional implants, the particles may have an effective average
particle size of less than about 400 nanometers, and in still
further embodiments, a size less than about 200 nanometers.
[0074] The steroid of the implant is preferably from about 10 to
90% by weight of the implant. More preferably, the steroid is from
about 50 to about 80% by weight of the implant. In a preferred
embodiment, the steroid comprises about 50% by weight of the
implant. In another embodiment, the steroid comprises about 70% by
weight of the implant.
[0075] Suitable polymeric materials or compositions for use in the
implant include those materials which are compatible, that is
biocompatible, with the eye so as to cause no substantial
interference with the functioning or physiology of the eye. Such
materials preferably are at least partially and more preferably
substantially completely biodegradable or bioerodible.
[0076] Examples of useful polymeric materials include, without
limitation, such materials derived from and/or including organic
esters and organic ethers, which when degraded result in
physiologically acceptable degradation products, including the
monomers. Also, polymeric materials derived from and/or including,
anhydrides, amides, orthoesters and the like, by themselves or in
combination with other monomers, may also find use. The polymeric
materials may be addition or condensation polymers, advantageously
condensation polymers. The polymeric materials may be cross-linked
or non-cross-linked, for example not more than lightly
cross-linked, such as less than about 5%, or less than about 1% of
the polymeric material being cross-linked. For the most part,
besides carbon and hydrogen, the polymers will include at least one
of oxygen and nitrogen, advantageously oxygen. The oxygen may be
present as oxy, e.g. hydroxy or ether, carbonyl, e.g.
non-oxo-carbonyl, such as carboxylic acid ester, and the like. The
nitrogen may be present as amide, cyano and amino. The polymers set
forth in Heller, Biodegradable Polymers in Controlled Drug
Delivery, In: CRC Critical Reviews in Therapeutic Drug Carrier
Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90, which
describes encapsulation for controlled drug delivery, may find use
in the present implants.
[0077] Of additional interest are polymers of hydroxyaliphatic
carboxylic acids, either homopolymers or copolymers, and
polysaccharides. Polyesters of interest include polymers of
D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid,
polycaprolactone, and combinations thereof. Generally, by employing
the L-lactate or D-lactate, a slowly eroding polymer or polymeric
material is achieved, while erosion is substantially enhanced with
the lactate racemate.
[0078] Among the useful polysaccharides are, without limitation,
calcium alginate, and functionalized celluloses, particularly
carboxymethylcellulose esters characterized by being water
insoluble, a molecular weight of about 5 kD to 500 kD, for
example.
[0079] Other polymers of interest include, without limitation,
polyvinyl alcohol, polyesters, polyethers and combinations thereof
which are biocompatible and may be biodegradable and/or
bioerodible.
[0080] Some preferred characteristics of the polymers or polymeric
materials for use in the present invention may include
biocompatibility, compatibility with the therapeutic component,
ease of use of the polymer in making the drug delivery systems of
the present invention, a half-life in the physiological environment
of at least about 6 hours, preferably greater than about one day,
not significantly increasing the viscosity of the vitreous, and
water insolubility.
[0081] The biodegradable polymeric materials which are included to
form the matrix are desirably subject to enzymatic or hydrolytic
instability. Water soluble polymers may be cross-linked with
hydrolytic or biodegradable unstable cross-links to provide useful
water insoluble polymers. The degree of stability can be varied
widely, depending upon the choice of monomer, whether a homopolymer
or copolymer is employed, employing mixtures of polymers, and
whether the polymer includes terminal acid groups.
[0082] Equally important to controlling the biodegradation of the
polymer and hence the extended release profile of the implant is
the relative average molecular weight of the polymeric composition
employed in the implant. Different molecular weights of the same or
different polymeric compositions may be included in the implant to
modulate the release profile. In certain implants, the relative
average molecular weight of the polymer will range from about 9 to
about 60 kD, usually from about 10 to about 54 kD, more usually
from about 12 to about 45 kD, and most usually less than about 40
kD.
[0083] In some implants, copolymers of glycolic acid and lactic
acid are used, where the rate of biodegradation is controlled by
the ratio of glycolic acid to lactic acid. The most rapidly
degraded copolymer has roughly equal amounts of glycolic acid and
lactic acid. Homopolymers, or copolymers having ratios other than
equal, are more resistant to degradation. The ratio of glycolic
acid to lactic acid will also affect the brittleness of the
implant, where a more flexible implant is desirable for larger
geometries. The % of polylactic acid in the polylactic acid
polyglycolic acid (PLGA) copolymer can be 0-100%, preferably about
15-85%, more preferably about 35-65%. In some implants, a 50/50
PLGA copolymer is used.
[0084] The biodegradable polymer matrix of the intraocular implant
may comprise a mixture of two or more biodegradable polymers. For
example, the implant may comprise a mixture of a first
biodegradable polymer and a different second biodegradable polymer.
One or more of the biodegradable polymers may have terminal acid
groups. In certain implants, the matrix comprises a first
biodegradable polymer having terminal acid groups, and a different
second biodegradable polymer having terminal acid groups. The first
biodegradable polymer may be a poly(D,L-lactide-co-glycolide). The
second biodegradable polymer may be a poly(D,L-lactide).
[0085] Release of a drug from an erodible polymer is the
consequence of several mechanisms or combinations of mechanisms.
Some of these mechanisms include desorption from the implants
surface, dissolution, diffusion through porous channels of the
hydrated polymer and erosion. Erosion can be bulk or surface or a
combination of both. As discussed herein, the matrix of the
intraocular implant may release drug at a rate effective to sustain
release of a therapeutically effective amount of the steroid for
more than three months after implantation into an eye. In certain
implants, therapeutic amounts of the steroid are released for more
than four months after implantation. For example, an implant may
comprise fluocinolone, and the matrix of the implant degrades at a
rate effective to sustain release of a therapeutically effective
amount of fluocinolone for about three months after being placed in
an eye. As another example, the implant may comprise triamcinolone,
and the matrix releases drug at a rate effective to sustain release
of a therapeutically effective amount of triamcinolone for more
than three months, such as from about three months to about six
months.
[0086] The rate of release of a drug from an implant of the present
invention may be related to the physical structure of the implant.
In a simple but very useful embodiment, the biodegradable polymer
of the present invention may comprise a substantially homogeneous
matrix mixed with the active agent(s). upon drying and formulation
of the matrix into an intraocular implant, the active agent may be
substantially homogeneously distributed in the matrix. In such an
embodiment, the release characteristics of the drug is largely
determined by the nature of the solvent and the rate of degradation
of the matrix.
[0087] In another embodiment the implant may comprise layers or
shells of differently formulated biodegradable polymer with which
the therapeutic agent and/or auxiliary agent may be associated and
released. Concentrations of polymer, therapeutic agent and/or
auxiliary agent may differ between layers, or the biodegradable
polymer may be formulated to deliver such agents at different
rates, according to different release profiles, or over different
time periods that other layers, or than a core portion of the
implant. Each layer may be formulated differently than at least one
other layer, due, without limitation, to differences in drug
concentration within different layers, absence or presence of the
therapeutic agent and/or the auxiliary agent within different
layers; differences in the means by which the drug(s) is associated
with the polymer matrix in different layers, or the chemistry and
density of the biodegradable materials.
[0088] Thus, release of a drug from the present implants can be
related to the amount of a drug present in the implant and the
properties of the polymers of the implant, such as polymer
molecular weight and ratio of glycolic acid to lactic acid. In one
embodiment of the present implants, the drug or drugs, such as the
steroid and/or auxiliary agent, is released at a first rate for a
first time period that is substantially independent of the polymer
properties, and the drug or drugs is released at a second rate for
a second time period after the first time period that is dependent
on the polymer properties of the implant. For example, an implant
comprises a steroid and a polymeric component that releases the
steroid from the implant for a time period of about thirty days
primarily due to steroid dissolution, and releases the steroid from
the implant after thirty days primarily due to polymer
properties.
[0089] One example of the biodegradable intraocular implant
comprises a steroid (and/or auxiliary agent) associated with a
biodegradable polymer matrix, which comprises a mixture of
different biodegradable polymers. At least one of the biodegradable
polymers is a polylactide having a molecular weight less than 40
kD. Such a mixture is effective in sustaining release of a
therapeutically effective amount at least one agent(s) for a time
period greater than about two months from the time the implant is
placed in an eye. In certain embodiments, the polylactide has a
molecular weight less than 20 kD. In other embodiments, the
polylactide has a molecular weight of about 10 kD. The polylactide
may be a poly(D,L-lactide), and the polylactide may include
polymers having terminal free acid groups. In one particular
embodiment, the matrix of the implant comprises a mixture of
poly(lactide-co-glycolide) and polylactide. Each of the
poly(lactide-co-glycolide) and polylactide may have terminal free
acid groups.
[0090] Another example of a biodegradable intraocular implant
comprises a steroid (and/or auxiliary agent) associated with a
biodegradable polymer matrix, which comprises a mixture of
different biodegradable polymers, each biodegradable polymer having
an inherent viscosity from about 0.16 dl/g to about 0.24 dl/g. For
example, one of the biodegradable polymers may have an inherent
viscosity of about 0.2 dl/g. Or, the mixture may comprise two
different biodegradable polymers, and each of the biodegradable
polymers has an inherent viscosity of about 0.2 dl/g. The inherent
viscosities identified above may be determined in 0.1% chloroform
at 25.degree. C.
[0091] Other implants may include a biodegradable polymer matrix of
biodegradable polymers, at least one of the polymers having an
inherent viscosity of about 0.25 dl/g to about 0.35 dl/g.
Additional implants may comprise a mixture of biodegradable
polymers wherein each polymer has an inherent viscosity from about
0.50 dl/g to about 0.70 dl/g.
[0092] The release of the steroid (and/or auxiliary agent) from the
intraocular implant comprising a biodegradable polymer matrix may
include an initial burst of release followed by a gradual increase
in the amount of the agent released, or the release may include an
initial delay in release of the steroid followed by an increase in
release. When the implant is substantially completely degraded, the
percent of the agent that has been released is about one hundred.
Compared to existing implants, in one embodiment the implants
disclosed herein do not completely release, or release about 100%
of at least one agent (steroid and/or auxiliary agent), until after
about two months of being placed in an eye. Thus, the implants
exhibit a cumulative release profile that may have a shallower
slope, or a lower rate of release, for longer periods of time than
existing implants.
[0093] In at least one embodiment, the present implants release an
active agent into the interior of the eye in an amount having a
reduced toxicity relative to bolus or liquid injections of the same
agent without a polymeric component. For example, it has been
reported that a single or repeated 20 mg dose of Kenalog 40 results
in substantial retinal changes, including changes in the retinal
pigment epithelium. Such doses may be necessary in liquid
formulations to provide prolonged therapeutic effects.
[0094] In comparison, the present implants can provide
therapeutically effective amounts of the steroid for prolonged
periods of time, or for a series of such time periods, without
requiring such large doses. Thus, present implants may contain 1
mg, 2 mg, 3 mg, 4 mg, or 5 mg of a steroid, such as triamcinolone
acetonide or fluocinolone acetonide, the steroid is gradually
released over time without causing substantial ocular toxicity or
other adverse side effects that are associated with injection of 20
mg of the steroid in a liquid formulation. The steroid may, in one
embodiment, be alternated within different shells of the implant
such that it is delivered only over particular time periods, with
time periods of substantially less (or no) steroid being delivered
intervening. In this way continued exposure of the eye to the
steroid, and the side effects that may accompany such constant
delivery, may be avoided or reduced. In another embodiment, an
intravitreal implant comprises triamcinolone acetonide and a
biodegradable polymer associated with the triamcinolone acetonide
in the form of an intravitreal implant that releases the
triamcinolone acetonide in amounts associated with a reduced
toxicity relative to the toxicity associated with administering
triamcinolone acetonide in a liquid composition.
[0095] It may be in certain cases desirable to provide a relatively
constant rate of release of the steroid from the implant over the
life of the implant. For example, it may be desirable for the
steroid to be released in amounts from about 0.01 .mu.g to about 2
.mu.g per day for the live of the implant. However, the release
rate may change to either increase or decrease depending on the
formulation of the biodegradable polymer matrix. In addition, the
release profile of the steroid may include one or more linear
portions and/or one or more non-linear portions. Preferably, the
release rate is greater than zero once the implant has begun to
degrade or erode.
[0096] It may be desirable to include delivery of an auxiliary
agent in conjunction with the intravitreal or subconjunctival
delivery of a steroid in order to reduce or eliminate at least one
side effect compared to the delivery of the steroid in an otherwise
identical manner without the auxiliary agent. The auxiliary agent
and steroid may be included in the same implant or coadministered
in different implants during the same treatment period.
[0097] The implants may be monolithic, i.e. having the active agent
or agents homogenously distributed through the polymeric matrix, or
encapsulated, where a reservoir of active agent is encapsulated by
the polymeric matrix. Due to ease of manufacture, monolithic
implants are usually preferred over encapsulated forms. However,
the greater control afforded by the encapsulated or reservoir-type
implant may be of benefit in some circumstances, where the
therapeutic level of the drug falls within a narrow window. In
addition, the therapeutic component, including the steroid, may be
distributed in a non-homogenous pattern in the matrix. For example,
the implant may include a portion that has a greater concentration
of the steroid and/or auxiliary agent relative to a second portion
of the implant.
[0098] In another embodiment of the present invention, an
intraocular implant comprises a therapeutic component, including a
steroid, and a drug release sustaining component including one or
more coating covering a core region of the implant. The therapeutic
component and/or auxiliary agent is provided in the core region.
The polymeric outer layer may be relatively impermeable to the
therapeutic component and ocular fluids. Or, the polymeric outer
layer may be initially impermeable to the therapeutic component and
ocular fluids, but then may become permeable to the therapeutic
component or ocular fluids as the outer layer degrades. Thus, the
polymeric outer layer may comprise a polymer such as
polytetrafluoroethylene, polyfluorinated ethylenepropylene,
polylactic acid, polyglycolic acid, silicone, or mixtures
thereof.
[0099] The foregoing implant may be understood to include a
reservoir of one or more therapeutic agents, such as a steroid
and/or auxiliary agent. In certain implants, the steroid may be a
corticosteroid, such as fluocinolone or triamcinolone, as discussed
above. One example of an implant including a reservoir of a
therapeutic agent is described in U.S. Pat. No. 6,331,313.
[0100] In some implants, the drug release sustaining component
comprises a polymeric outer layer covering the therapeutic
component and or the auxiliary agent, the outer layer comprises a
plurality of openings or holes through which the therapeutic
component may pass from the drug delivery system to an external
environment of the implant, such as an ocular region of an eye. The
holes enable a liquid to enter into the interior of the implant and
dissolve the agent contained therein. The release of the
therapeutic agent and/or auxiliary agent from the implant may be
influenced by the drug solubility in the liquid, the size of the
hole(s), and the number of holes. In certain implants, the hole
size and number of holes are effective in providing substantially
all of the desired release characteristics of the implant. Thus,
additional excipients may not be necessary to achieve the desired
results. However, in other implants, excipients may be provided to
further augment the release characteristics of the implant.
[0101] Various biocompatible substantially impermeable polymeric
compositions may be employed in preparing the outer layer of the
implant. Some relevant factors to be considered in choosing a
polymeric composition include: compatibility of the polymer with
the biological environment of the implant, compatibility of the
drug with the polymer, ease of manufacture, a half-life in the
physiological environment of at least several days, no significant
enhancement of the viscosity of the vitreous, and the desired rate
of release of the drug. Depending on the relative importance of
these characteristics, the compositions can be varied. Several such
polymers and their methods of preparation are well-known in the
art. See, for example, U.S. Pat. Nos. 4,304,765; 4,668,506
4,959,217; 4,144,317, and 5,824,074, Encyclopedia of Polymer
Science and Technology, Vol. 3, published by Interscience
Publishers, Inc., New York, latest edition, and Handbook of Common
Polymers by Scott, J. R. and Roff, W. J., published by CRC Press,
Cleveland, Ohio, latest edition.
[0102] The polymers of interest may be homopolymers, copolymers,
straight, branched-chain, or cross-linked derivatives. Some
exemplary polymers include: polycarbamates or polyureas,
cross-linked poly(vinyl acetate) and the like, ethylene-vinyl ester
copolymers having an ester content of 4 to 80% such as
ethylene-vinyl acetate (EVA) copolymer, ethylene-vinyl hexanoate
copolymer, ethylene-vinyl propionate copolymer, ethylene-vinyl
butyrate copolymer, ethylene-vinyl pentantoate copolymer,
ethylene-vinyl trimethyl acetate copolymer, ethylene-vinyl diethyl
acetate copolymer, ethylene-vinyl 3-methyl butanoate copolymer,
ethylene-vinyl 3-3-dimethyl butanoate copolymer, and ethylene-vinyl
benzoate copolymer, or mixtures thereof.
[0103] Additional examples include polymers such as:
poly(methylmethacrylate), poly(butylnethacrylate), plasticized
poly(vinylchloride), plasticized poly(amides), plasticized nylon,
plasticized soft nylon, plasticized poly(ethylene terephthalate),
natural rubber, silicone, poly(isoprene), poly(isobutylene),
poly(butadiene), poly(ethylene), poly(tetrafluoroethylene),
poly(vinylidene chloride), poly(acrylonitrile, cross-linked
poly(vinylpyrrolidone), chlorinated poly(ethylene),
poly(trifluorochloroethylene), poly(ethylene
chlorotrifluoroethylene), poly(tetrafluoroethylene), poly(ethylene
tetrafluoroethylene), poly(4,4'-isopropylidene diphenylene
carbonate), polyurethane, poly(perfluoroalkoxy),
poly(vinylidenefluoride), vinylidene chloride-acrylonitrile
copolymer, vinyl chloride-diethyl fumarate copolymer, silicone,
silicone rubbers (of medical grade such as Silastic.RTM. Medical
Grade ETR Elastomer Q7-4750 or Dow Corning.RTM. MDX 4-4210 Medical
Grade Elastomer); and cross-linked copolymers of polydimethylsilane
silicone polymers.
[0104] Some further examples of polymers include:
poly(dimethylsiloxanes), ethylene-propylene rubber,
silicone-carbonate copolymers, vinylidene chloride-vinyl chloride
copolymer, vinyl chloride-acrylonitrile copolymer, vinylidene
chloride-acrylonitrile copolymer, poly(olefins),
poly(vinyl-olefins), poly(styrene), poly(halo-olefins),
poly(vinyls) such as polyvinyl acetate, cross-linked polyvinyl
alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate
copolymer, polyethyl hexylacrylate, polyvinyl chloride, polyvinyl
acetals, plasticized ethylene vinylacetate copolymer, polyvinyl
alcohol, polyvinyl acetate, ethylene vinylchloride copolymer,
polyvinyl esters, polyvinylbutyrate, polyvinylformal,
poly(acrylate), poly(methacrylate), poly(oxides), poly(esters),
poly(amides), and poly(carbonates), or mixtures thereof.
[0105] In some aspects, the implants with an outer layer coating
with holes may be biodegradable wherein the outer layer degrades
after the drug has been released for the desired duration. The
biodegradable polymeric compositions may comprise any of the
above-identified biodegradable polymers or combinations thereof. In
some implants, the polymer is polytetrafluoroethylene,
(commercially known as Teflon.RTM.), ethyl vinyl alcohol or
ethylene vinyl acetate.
[0106] The steroid containing implants typically exhibited
desirable release times with orifices configured to have a total
area of less than 1% of the total surface area of the implant. A
substantially cylindrically shaped implant has a first end, a
second end, and a body portion between the first end and the second
end. Typically, the implants disclosed herein are sealed at the
first and second ends. One or more holes are formed in the body
portion of the implant. The holes typically have a diameter of at
least about 250 .mu.m and less than about 500 .mu.m. For example,
holes may have a diameter of about 250 .mu.m, 325 .mu.m, 375 .mu.m,
or 500 .mu.m. Smaller holes may be provided in other implants.
Typically, two or three holes are provided in the implant outer
layer. The holes may be spaced apart by a distance from about 1 mm
to about 2 mm for implants having a length of about 7 mm to about
10 mm.
[0107] In one steroid-containing implant, the total area of the
holes was about 0.311% of the total surface area of the implant. In
another steroid-containing implant, the total area of the holes was
about 0.9% of the total surface area of the implant. The area of an
orifice or hole is determined by the following formula:
Area=3.1416.times.r.sup.2
[0108] where r is the radius of the orifice. The area for each
orifice may be determined and added together to determine the total
orifice area. The tubular implant surface area may be determined by
the following formula:
Surface
area=3.1416.times.OD.times.length+2.times.3.1416r.sub.od.sup.2
[0109] where OD is the outer diameter of a cross-section of the
tubular implant, length is the length of the tubular implant, and
r.sub.od is the radius of the cross-section of the tubular
implant.
[0110] In the configurations described above, the implant is
capable of releasing the steroid at concentrations less than 2
.mu.g/day. Some implants were capable of releasing the steroid at a
concentration of about 0.5 .mu.g/day. These implants are capable of
providing therapeutically effective amounts of the steroid to an
ocular region of an eye for more than one year, such as for more
than five years, and even for about 13 years.
[0111] Examples of materials used and methods of making such
implants are disclosed in U.S. Pat. No. 6,331,313. Briefly, a
coating is formed around a core containing a therapeutic agent. The
core may include a therapeutic agent (or a therapeutic component
and an auxiliary agent) associated with a biodegradable polymer
matrix, or the core may be formed by filling a preformed coating,
such as a tube.
[0112] The therapeutic agent and auxiliary agent can each be
deposited in a preformed coating as a dry powder, particles,
granules, or as a compressed solid. The agent or agents may also be
present in a solution. In addition, the core can comprise a mixture
of a biodegradable polymer matrix and the agent or agents, such as
the matrix containing implants described above. The polymers used
in the matrix with the therapeutic agent and/or auxiliary agent are
bio-compatible with body tissues and body fluids and can be
biodegradable or substantially insoluble in the body fluids. Any of
the above-described biocompatible polymer compositions can be used
to prepare the matrix. The amount of polymer in the core may be
from about 0% to 80 wt % by weight. These polymers are commercially
available and methods for preparing polymer matrices are well-known
in the art. See, for example, U.S. Pat. No. 5,882,682.
[0113] The biocompatible, substantially impermeable outer layer can
be obtained by coating the core with a polymeric composition
described above. The coat can be applied using organic solvents,
and the solvents may then be vacuum stripped from the coat to leave
a dry coat. The polymer, at a concentration of from about 10 to
about 80 weight percent is dissolved or suspended in an organic
solvent at the appropriate temperature, for example for polylactic
polymer, between 60 degrees to 90 degrees C. The resulting mixture
can be cut, molded, injection molded, extruded, or poured or
sprayed onto a pre-formed core into any shape or size for
implantation. The spraying can be accomplished in a rotating pan
coater or in a fluidized bed coater until the desired coating
thickness is achieved.
[0114] Alternatively, the core may be dip coated or melt coated.
This type of coating is especially useful with waxes and oils. In
another embodiment, the core may be compression coated, wherein a
suitable polymeric composition may be pressed onto a preformed
core. In another aspect, an adhesive coat such as shellac or
polyvinyl acetate phthalate (PVAP) is applied to the core prior to
applying the impermeable coating in order to improve adhesion of
the impermeable coating to the core. These techniques are
well-known in the art. See, for example, Handbook of Common
Polymers, by J. R. Scott and W. J. Roff, Section 64, (1971)
published by CRC Press, Cleveland, Ohio.
[0115] When the outer layer is injection molded or extruded into
the desired shape, the cavity formed by the outer layer can be then
filled with the therapeutic agent and/or auxiliary agent
composition. Then, the ends are sealed with an end cap. At least
one orifice is drilled in the device. Optionally, an orifice is
drilled, or preformed in the wall, or an orifice is sealed with a
break-off tab that is broken open, or cut open, or the like, at the
time of use.
[0116] Alternatively, the core-free device may be loaded with
therapeutic agent by, for example, immersing the device in a
solution comprising the therapeutic agent for a time sufficient for
absorption of the therapeutic agent. The device may be equipped
with a hollow fiber and the therapeutic agent and/or auxiliary
agent may be directly loaded into the fiber and the device
subsequently sealed. Where the activity of the therapeutic agent
and/or auxiliary agent will not be compromised, the therapeutic
agent-filled device may then be dried or partially dried for
storage until use. This method may find particular application
where the activity of the therapeutic agent of choice is sensitive
to exposure to solvents, heat or other aspects of the conventional
solvent-evaporation, molding, extrusion or other methods described
above.
[0117] The orifice may be formed using any technique known in the
art. For instance, the orifice may be made using a needle or other
form of boring instrument such as a mechanical drill or a laser to
remove a section of the impermeable portion of the device.
Alternatively, a specially designed punch tip may be incorporated
into the compressing equipment, in order to pierce through the
impermeable portion at the point of compaction.
[0118] The holes may be made by drilling the appropriate size hole
through a wall of the device using a mechanical or laser-based
process. In some implants, a digital laser marking system is used
to drill the holes. This system allows for an array of apertures to
be drilled on both faces of a dosage form simultaneously and at
rates suitable for production of dosage forms. The process utilizes
a digital laser marking system (for example the DigiMark.TM.
variable marking system, available from Directed Energy, Inc.) to
produce an unlimited number of holes through the surface or coating
of the dosage form, at rates practically suitable for production of
dosage forms.
[0119] The steps involved in this laser drilling process are as
follows: a digital laser marking system is focused at a laser
stage; the dosage form is moved onto the laser stage of the digital
laser marking system is pulsed to energize those laser tubes needed
to drill the desired apertures along a linear array on the dosage
form, the dosage form is moved forward on the laser stage and the
digital laser marking system is again pulsed as needed to produce
an additional linear array of apertures; the dosage form is then
removed from the laser stage.
[0120] Orifices and equipment for forming orifices are disclosed in
U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064 and 4,008,864.
Orifices formed by leaching are disclosed in U.S. Pat. Nos.
4,200,098 and 4,285,987. Laser drilling machines equipped with
photo wave length detecting systems for orienting a device are
described in U.S. Pat. No. 4,063,064 and in U.S. Pat. No.
4,088,864.
[0121] The intraocular implants disclosed herein may have a size of
between about 5 .mu.m and about 10 mm, or between about 10 .mu.m
and about 1 mm for administration with a needle, greater than 1 mm,
or greater than 2 mm, such as 3 mm or up to 10 mm, for
administration by surgical implantation. For needle-injected
implants, the implants may have any appropriate length so long as
the diameter of the implant permits the implant to move through a
needle. For example, implants having a length of about 6 mm to
about 7 mm have been injected into an eye. The implants
administered by way of a needle should have a diameter that is less
than the inner diameter of the needle. In certain implants, the
diameter is less than about 500 .mu.m. The vitreous chamber in
humans is able to accommodate relatively large implants of varying
geometries, having lengths of, for example, 1 to 10 mm. The implant
may be a cylindrical pellet (e.g., rod) with dimensions of about 2
mm.times.0.75 mm diameter. Or the implant may be a cylindrical
pellet with a length of about 7 mm to about 10 mm, and a diameter
of about 0.75 mm to about 1.5 mm.
[0122] The implants may also be at least somewhat flexible so as to
facilitate both insertion of the implant in the eye, such as in the
vitreous, and accommodation of the implant. The total weight of the
implant is usually about 250-5000 .mu.g, more preferably about
500-1000 .mu.g. For example, an implant may be about 500 .mu.g, or
about 1000 .mu.g. For non-human individuals, the dimensions and
total weight of the implant(s) may be larger or smaller, depending
on the type of individual. For example, humans have a vitreous
volume of approximately 3.8 ml, compared with approximately 30 ml
for horses, and approximately 60-100 ml for elephants. An implant
sized for use in a human may be scaled up or down accordingly for
other animals, for example, about 8 times larger for an implant for
a horse, or about, for example, 26 times larger for an implant for
an elephant.
[0123] Thus, implants can be prepared where the center may be of
one material and the surface may have one or more layers of the
same or a different composition, where the layers may be
cross-linked, or of a different molecular weight, different density
or porosity, or the like. For example, where it is desirable to
quickly release an initial bolus of drug, the center may be a
polylactate coated with a polylactate-polyglycolate copolymer, so
as to enhance the rate of initial degradation. Alternatively, the
center may be polyvinyl alcohol coated with polylactate, so that
upon degradation of the polylactate exterior the center would
dissolve and be rapidly washed out of the eye.
[0124] The implants, particularly the implants with the steroid
and/or auxiliary agent associated with a biodegradable polymer
matrix, may be of any geometry including fibers, sheets, films,
microspheres and microparticles, spheres, circular discs, plaques
and the like. The upper limit for the implant size will be
determined by factors such as toleration for the implant, size
limitations on insertion, ease of handling, etc. Where sheets or
films are employed, the sheets or films will be in the range of at
least about 0.5 mm.times.0.5 mm, usually about 3-10 mm.times.5-10
mm with a thickness of about 0.1-1.0 mm for ease of handling. Where
fibers are employed, the fiber diameter will generally be in the
range of about 0.05 to 3 mm and the fiber length will generally be
in the range of about 0.5-10 mm. Spheres may be in the range of
about 0.5 .mu.m to 4 mm in diameter, with comparable volumes for
other shaped particles.
[0125] In certain embodiments of the present invention the use if
microsphere implants may be particularly advantageous. A method of
making such microspheres involves combining, associating or mixing
the therapeutic and/or auxiliary agent with a biodegradable polymer
or polymers. The mixture may then be extruded or compressed to form
a single composition. The single composition may then be processed
to form microspheres suitable for placement intravitreally or
subconjunctivally.
[0126] Alternatively, a method of making the present microspheres
may also include using an oil-in-oil emulsion process to form the
microspheres. Such methods may be particularly useful in forming
microparticles, nanoparticles and the like. Thus, an embodiment of
the present invention relates to the inserts comprising
microparticles made using an oil-in-oil emulsion process.
[0127] The microspheres, which may include a population of
microparticles or nanoparticles, may be placed in an ocular region
such as, without limitation, intravirtreally or subconjunctivally,
to treat a variety of ocular conditions. For example, the
microspheres may be administered intravitreally in a manner
effective to delivering a therapeutic component and/or auxiliary
agent to tissues of the posterior segment, thereby reducing damage
to the tissues of the posterior segment while reducing at least one
side effect as compared to the administration of the steroid alone
in an otherwise identical manner. Alternatively, subconjunctival
administration of the microspheres of the present invention are
very effective at delivering the therapeutic component to the
retina and other tissues of the posterior segment for the treatment
of neurodegenerative conditions such as age related macular
degeneration (ARMD), such as "wet" or "dry" ARMD, macular edema,
etc.
[0128] The use of microspheres, microparticles and the like
provides an excellent means of punctuated delivery of the steroid
in the implants of the present invention. For example, in one
embodiment different lots (comprising the same or different sizes
of microparticles) are made, each having a different property, such
as different rates of erosion; different drug content (for example
some may contain a steroid and an auxiliary agent, while others may
just contain the auxiliary agent; some may be made of one
bioerodable polymer having a fast dissolution rate, while others
may be made of a different biopolymer having a slower dissolution
rate. By engineering the microparticles so that during the
treatment period the dosage of steroid is "pulsed", for example,
from an initial substantially optimal therapeutically effective
dosage to a subsequent period lacking a substantially optimal
therapeutically effective dosage of the steroid and optionally to
another treatment time period in which a substantially optimal
therapeutically effective dosage of the steroid is again
administered, at least one of the deleterious side effects of long
term steroid use can be lessened. Some microspheres may, for
example, be loaded with the auxiliary agent, either alone or in
combination with the steroid, to provide a substantially constant
(or at least slowly decaying) dosage of the auxiliary agent to
ocular tissues during the treatment period, while the dosage of
steroid may vary.
[0129] Thus, the combination of different microspheres in a
discretely administered intravitreal or subconjunctival injection
or insertion provides a powerful way to separately tailor the
administration of steroid and auxiliary agent. Methods of making
microspheres are provided in U.S. application Ser. No. 11/303,462,
and U.S. application Ser. No. 10/837,260, under common ownership
with the present application, the entire contents of both of which
prior applications are hereby incorporated by reference.
[0130] The size and form of the implant can also be used to control
the rate of release, period of treatment, and drug concentration at
the site of implantation. Larger implants will deliver a
proportionately larger dose, but depending on the surface to mass
ratio, may have a slower release rate. The particular size and
geometry of the implant are chosen to suit the site of
implantation.
[0131] The proportions of steroid and/or auxiliary agent, polymer,
and any other modifiers may be empirically determined by
formulating several implants with varying proportions. A USP
approved method for dissolution or release test can be used to
measure the rate of release (USP 23; NF 18 (1995) pp. 1790-1798).
For example, using the infinite sink method, a weighed sample of
the implant is added to a measured volume of a solution containing
0.9% NaCl in water, where the solution volume will be such that the
drug concentration is after release is less than 5% of saturation.
The mixture is maintained at 37.degree. C. and stirred slowly to
maintain the implants in suspension. The appearance of the
dissolved drug as a function of time may be followed by various
methods known in the art, such as spectrophotometrically, HPLC,
mass spectroscopy, etc. until the absorbance becomes constant or
until greater than 90% of the drug has been released.
[0132] In addition to the steroid or steroids included in the
intraocular implants disclosed herein, the intraocular implants may
also include one or more additional ophthalmically acceptable
therapeutic agents. For example, the implant may include one or
more antihistamines, one or more antibiotics, one or more beta
blockers, one or more different corticosteroids, one or more
neuroprotectant agent, one or more anti-glaucoma agent, one or more
antibiotic, one or more antineoplastic agents, one or more
immunosuppressive agents, one or more antiviral agents, one or more
antioxidant agents, and mixtures thereof.
[0133] Pharmacologic or therapeutic agents which may find use in
the present systems, include, without limitation, those disclosed
in U.S. Pat. No. 4,474,451, columns 4-6 and U.S. Pat. No.
4,327,725, columns 7-8.
[0134] Examples of antihistamines include, and are not limited to,
loradatine, hydroxyzine, diphenhydramine, chlorpheniramine,
brompheniramine, cyproheptadine, terfenadine, clemastine,
triprolidine, carbinoxamine, diphenylpyraline, phenindamine,
azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine,
methdilazine, and trimprazine doxylamine, pheniramine, pyrilamine,
chiorcyclizine, thonzylamine, and derivatives thereof.
[0135] Examples of antibiotics include without limitation,
cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime,
cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil,
ceftazidime, cephalexin, cephalothin, cefamandole, cefoxitin,
cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine,
cefuroxime, ampicillin, amoxicillin, cyclacillin, ampicillin,
penicillin G, penicillin V potassium, piperacillin, oxacillin,
bacampicillin, cloxacillin, ticarcillin, azlocillin, carbenicillin,
methicillin, nafcillin, erythromycin, tetracycline, doxycycline,
minocycline, aztreonam, chloramphenicol, ciprofloxacin
hydrochloride, clindamycin, metronidazole, gentamicin, lincomycin,
tobramycin, vancomycin, polymyxin B sulfate, colistimethate,
colistin, azithromycin, augmentin, sulfamethoxazole, trimethoprim,
ofloxacin, ciprofloxacin, norfloxacin, and derivatives thereof.
[0136] Examples of beta blockers include acebutolol, atenolol,
labetalol, metoprolol, propranolol, timolol, and derivatives
thereof.
[0137] Examples of other corticosteroids include cortisone,
prednisolone, flurometholone, dexamethasone, medrysone,
loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone,
prednisone, methylprednisolone, riamcinolone hexacatonide,
paramethasone acetate, diflorasone, fluocinonide, derivatives
thereof, and mixtures thereof.
[0138] Examples of antineoplastic agents include adriamycin,
cyclophosphamide, actinomycin, bleomycin, duanorubicin,
doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil,
carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide,
interferons, camptothecin and derivatives thereof, phenesterine,
taxol and derivatives thereof, taxotere and derivatives thereof,
vinblastine, vincristine, tamoxifen, etoposide, piposulfan,
cyclophosphamide, and flutamide, and derivatives thereof.
[0139] Examples of immunosuppressive agents include cyclosporine,
azathioprine, tacrolimus, and derivatives thereof.
[0140] Examples of antiviral agents include interferon gamma,
zidovudine, amantadine hydrochloride, ribavirin, acyclovir,
valciclovir, dideoxycytidine, phosphonoformic acid, ganciclovir,
and derivatives thereof.
[0141] Examples of antioxidant agents include ascorbate,
alpha-tocopherol, mannitol, reduced glutathione, various
carotenoids, cysteine, uric acid, taurine, tyrosine, superoxide
dismutase, lutein, zeaxanthin, cryotpxanthin, astazanthin,
lycopene, N-acetyl-cysteine, carnosine, gamma-glutamylcysteine,
quercitin, lactoferrin, dihydrolipoic acid, citrate, Ginkgo Biloba
extract, tea catechins, bilberry extract, vitamins E or esters of
vitamin E, retinyl palmitate, and derivatives thereof.
[0142] Other therapeutic agents include squalamine, carbonic
anhydrase inhibitors, alpha agonists, prostamides, neuroprotectants
such as NMDA receptor antagonists and alpha 2 adrenergic agonists,
prostaglandins, antiparasitics, antifungals, and derivatives
thereof.
[0143] The amount of active agent or agents employed in the
implant, individually or in combination, will vary widely depending
on the effective dosage required and the desired rate of release
from the implant. Usually the agent will be at least about 1, more
usually at least about 10 weight percent of the implant, and
usually not more than about 80, more usually not more than about 40
weight percent of the implant.
[0144] In addition to the therapeutic component and/or auxiliary
agent, the intraocular implants disclosed herein may include
effective amounts of buffering agents, preservatives and the like.
Suitable water soluble buffering agents include, without
limitation, alkali and alkaline earth carbonates, phosphates,
bicarbonates, citrates, borates, acetates, succinates and the like,
such as sodium phosphate, citrate, borate, acetate, bicarbonate,
carbonate and the like. These agents advantageously present in
amounts sufficient to maintain a pH of the system of between about
2 to about 9 and more preferably about 4 to about 8. As such the
buffering agent may be as much as about 5% by weight of the total
implant. Suitable water soluble preservatives include sodium
bisulfite, sodium bisulfate, sodium thiosulfate, ascorbate,
benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric
acetate, phenylmercuric borate, phenylmercuric nitrate, parabens,
methylparaben, polyvinyl alcohol, benzyl alcohol, phenylethanol and
the like and mixtures thereof. These agents may be present in
amounts of from 0.001 to about 5% by weight and preferably 0.01 to
about 2% by weight.
[0145] In some situations mixtures of implants may be utilized
employing the same or different pharmacological agents. In this
way, a cocktail of release profiles, giving a multiphasic release
with a single administration is achieved, where the pattern of
release may be greatly varied.
[0146] Additionally, release modulators such as those described in
U.S. Pat. No. 5,869,079 may be included in the implants. The amount
of release modulator employed will be dependent on the desired
release profile, the activity of the modulator, and on the release
profile of the glucocorticoid in the absence of modulator.
Electrolytes such as sodium chloride and potassium chloride may
also be included in the implant. Where the buffering agent or
enhancer is hydrophilic, it may also act as a release accelerator.
Hydrophilic additives act to increase the release rates through
faster dissolution of the material surrounding the drug particles,
which increases the surface area of the drug exposed, thereby
increasing the rate of drug bioerosion. Similarly, a hydrophobic
buffering agent or enhancer dissolve more slowly, slowing the
exposure of drug particles, and thereby slowing the rate of drug
bioerosion.
[0147] Various techniques may be employed to produce the implants
described herein. Useful techniques include, but are not
necessarily limited to, solvent evaporation methods, phase
separation methods, interfacial methods, molding methods, injection
molding methods, extrusion methods, co-extrusion methods, carver
press method, die cutting methods, heat compression, combinations
thereof and the like.
[0148] Specific methods are discussed in U.S. Pat. No. 4,997,652.
Extrusion methods may be used to avoid the need for solvents in
manufacturing. When using extrusion methods, the polymer and drug
are chosen so as to be stable at the temperatures required for
manufacturing, usually at least about 85 degrees Celsius. Extrusion
methods use temperatures of about 25 degrees C. to about 150
degrees C., more preferably about 65 degrees C. to about 130
degrees C. An implant may be produced by bringing the temperature
to about 60 degrees C. to about 150 degrees C. for drug/polymer
mixing, such as about 130 degrees C., for a time period of about 0
to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, a time
period may be about 10 minutes, preferably about 0 to 5 min. The
implants are then extruded at a temperature of about 60 degrees C.
to about 130 degrees C., such as about 75 degrees C.
[0149] In addition, the implant may be coextruded so that a coating
is formed over a core region during the manufacture of the
implant.
[0150] Compression methods may be used to make the implants, and
typically yield implants with faster release rates than extrusion
methods. Compression methods may use pressures of about 50-150 psi,
more preferably about 70-80 psi, even more preferably about 76 psi,
and use temperatures of about 0 degrees C. to about 115 degrees C.,
more preferably about 25 degrees C.
[0151] The implants of the present invention may be inserted into
the eye, for example the vitreous chamber of the eye, by a variety
of methods, including placement by forceps or by trocar following
making a 2-3 mm incision in the sclera. The method of placement may
influence the therapeutic component or drug release kinetics. For
example, delivering the implant with a trocar may result in
placement of the implant deeper within the vitreous than placement
by forceps, which may result in the implant being closer to the
edge of the vitreous. The location of the implant may influence the
concentration gradients of therapeutic component or drug
surrounding the element, and thus influence the release rates
(e.g., an element placed closer to the edge of the vitreous may
result in a slower release rate).
[0152] The implants of the present invention may also, or
alternatively, be inserted into the subconjunctival space such as
by injection or surgical insertion. Applicants are aware that
effective retinal delivery is effectively provided by such
subconjunctival administration.
[0153] Among the diseases/conditions which can be treated or
addressed in accordance with the present invention include, without
limitation, the following:
[0154] MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age
Related Macular Degeneration (ARMD), Exudative Age Related Macular
Degeneration (ARMD), Choroidal Neovascularization, Diabetic
Retinopathy, Acute Macular Neuroretinopathy, Central Serous
Chorioretinopathy, Cystoid Macular Edema, Diabetic Macular
Edema.
[0155] UVEITIS/RETINITIS/CHOROIDITIS: Acute Multifocal Placoid
Pigment Epitheliopathy, Behcet's Disease, Birdshot
Retinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis,
Toxoplasmosis), Intermediate Uveitis (Pars Planitis), Multifocal
Choroiditis, Multiple Evanescent White Dot Syndrome (MEWDS), Ocular
Sarcoidosis, Posterior Scleritis, Serpignous Choroiditis,
Subretinal Fibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada
Syndrome.
[0156] VASCULAR DISEASES/EXUDATIVE DISEASES: Retinal Arterial
Occlusive Disease, Central Retinal Vein Occlusion, Disseminated
Intravascular Coagulopathy, Branch Retinal Vein Occlusion,
Hypertensive Fundus Changes, Ocular Ischemic Syndrome, Retinal
Arterial Microaneurysms, Coat's Disease, Parafoveal Telangiectasis,
Hemi-Retinal Vein Occlusion, Papillophlebitis, Central Retinal
Artery Occlusion, Branch Retinal Artery Occlusion, Carotid Artery
Disease (CAD), Frosted Branch Angitis, Sickle Cell Retinopathy and
other Hemoglobinopathies, Angioid Streaks, Familial Exudative
Vitreoretinopathy, Eales Disease.
[0157] TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal
Disease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation,
Hypoperfusion During Surgery, Radiation Retinopathy, Bone Marrow
Transplant Retinopathy.
[0158] PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy
and Epiretinal Membranes, Proliferative Diabetic Retinopathy.
[0159] INFECTIOUS DISORDERS: Ocular Histoplasmosis, Ocular
Toxocariasis, Presumed Ocular Histoplasmosis Syndrome (PONS),
Endophthalmitis, Toxoplasmosis, Retinal Diseases Associated with
HIV Infection, Choroidal Disease Associated with HIV Infection,
Uveitic Disease Associated with HIV Infection, Viral Retinitis,
Acute Retinal Necrosis, Progressive Outer Retinal Necrosis, Fungal
Retinal Diseases, Ocular Syphilis, Ocular Tuberculosis, Diffuse
Unilateral Subacute Neuroretinitis, Myiasis.
[0160] GENETIC DISORDERS: Retinitis Pigmentosa, Systemic Disorders
with Associated Retinal Dystrophies, Congenital Stationary Night
Blindness, Cone Dystrophies, Stargardt's Disease and Fundus
Flavimaculatus, Best's Disease, Pattern Dystrophy of the Retinal
Pigmented Epithelium, X-Linked Retinoschisis, Sorsby's Fundus
Dystrophy, Benign Concentric Maculopathy, Bietti's Crystalline
Dystrophy, pseudoxanthoma elasticum.
[0161] RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant
Retinal Tear.
[0162] TUMORS: Retinal Disease Associated with Tumors, Congenital
Hypertrophy of the RPE, Posterior Uveal Melanoma, Choroidal
Hemangioma, Choroidal Osteoma, Choroidal Metastasis, Combined
Hamartoma of the Retina and Retinal Pigmented Epithelium,
Retinoblastoma, Vasoproliferative Tumors of the Ocular Fundus,
Retinal Astrocytoma, Intraocular Lymphoid Tumors.
[0163] MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior
Multifocal Placoid Pigment Epitheliopathy, Myopic Retinal
Degeneration, Acute Retinal Pigment Epithelitis and the like.
[0164] In one embodiment, an implant, such as the implants
disclosed herein, is administered to a posterior segment of an eye
of a human or animal patient, and preferably, a living human or
animal. In at least one embodiment, an implant is administered
without accessing the subretinal space of the eye. For example, a
method of treating a patient may include placing the implant
directly into the posterior chamber of the eye. In other
embodiments, a method of treating a patient may comprise
administering an implant to the patient by at least one of
intravitreal injection, subconjuctival injection, sub-tenon
injections, retrobulbar injection, and suprachoroidal
injection.
[0165] In at least one embodiment, a method of treating a posterior
ocular condition comprises administering one or more implants
containing one or more steroids, as disclosed herein to a patient
by at least one of intravitreal injection, subconjuctival
injection, sub-tenon injection, retrobulbar injection, and
suprachoroidal injection. A syringe apparatus including an
appropriately sized needle, for example, a 22 gauge needle, a 27
gauge needle or a 30 gauge needle, can be effectively used to
inject the composition with the posterior segment of an eye of a
human or animal. Repeat injections are often not necessary due to
the extended release of the steroid from the implants.
[0166] The present implants provide prolonged therapy to patients
in need of ocular therapy. As discussed herein, the present
implants can release a steroid for at least about 2 months after
placement in the vitreous of an eye of a patient. In certain
implants, the steroid, and/or other therapeutic agents, can be
released for at least about one year, for example for about three
years. In additional implants, the steroid and/or auxiliary agent
can be released at therapeutically effective amounts for more than
three years, such as for about five years.
[0167] In another aspect of the invention, kits for treating an
ocular condition of the eye are provided, comprising: a) a
container comprising an extended release implant comprising a
therapeutic component including a steroid, such as fluocinolone or
triamcinolone, an auxiliary agent, and optionally a drug release
sustaining component; and b) instructions for use. Instructions may
include steps of how to handle the implants, how to insert the
implants into an ocular region, and what to expect from using the
implants.
[0168] In view of the disclosure herein, one embodiment of a
biodegradable intraocular implant comprises a steroid, such as
triamcinolone acetonide, fluocinolone acetonide, dexamethasone, and
the like, optionally an auxiliary agent, and a biodegradable
polymeric component, and substantially no polyvinyl alcohol. Such
an implant may be useful in treating uveitis, including
non-infectious uveitis, and other ocular disorders, including
macular edema, age-related macular degeneration, and the disorders
described herein. Advantageously, these implants can be placed in
the vitreous of an eye of a patient, and can provide one or more
therapeutic benefits with relatively few or no side effects. For
example, the steroid, such as fluocinolone acetonide, can be
released from the implant without the patient developing cataracts,
vitreous hemorrhage, retinal neovascularization, and/or ocular
hypertension.
[0169] In another embodiment, the implant can comprise a steroid,
such as fluocinolone acetonide, optionally an auxiliary agent, and
the implant can have a form other than a tablet. For example, the
implant can be in the form of a rod, sphere, particle and the like.
In certain implants, the implant is an extruded element as compared
to a compressed tablet. The implant may include an adhesive
component effective in retaining the implant in a fixed position in
the eye. For example, certain implants, such as non-tablet
implants, may include a polyvinyl alcohol suture. Other implants,
including compressed tablets, may include an adhesive component
that is free of polyvinyl alcohol. For example, a hydrogel material
may be used to affix the implant in the eye of a patient.
[0170] In another embodiment, a steroid-containing intraocular
tablet may comprise a polyvinyl alcohol coating over the tablet
body, and be substantially free of a silicone component. Some
examples of useful coatings include those described above.
[0171] In a further embodiment, an implant can comprise a steroid,
such as fluocinolone acetonide or triamcinolone acetonide, and an
intraocular pressure reducing agent or antiglaucoma drug. These
implants may be particularly useful in preventing an increase in
intraocular pressure associated with release of the steroid from
the implant into the eye. The term antiglaucoma drug, as used
herein, is meant to include both the terms intraocular pressure
reducing agent and antiglaucoma drug.
[0172] It will be understood that antiglaucoma drugs need not
necessarily be ocular hypotensive drugs. Although elevated
intraocular pressure accompanies most cases of glaucoma, is not
always present. Thus, for example, "low-tension" or
"normal-tension" glaucoma is a condition that causes optic nerve
damage and narrowed side vision in people with normal eye pressure.
While lowering eye pressure helps at least 30 percent of these
patients slow the progression of the disease, glaucoma may worsen
in others despite low intraocular pressure.
[0173] Therefore, certain antiglaucoma drugs may have
neuroprotective activity in addition to, or instead of. ocular
hypotensive activity.
[0174] A wide range of antiglaucoma drugs may be utilized in the
ocular implants according to embodiments of the present invention.
For example, six types of antiglaucoma drugs are listed on the
website of the New York Glaucoma Research Institute (NYGRI),
www.glaucoma.net/nygri/glaucoma/topics/drugs.html. It will be
understood that this classification of antiglaucoma drugs contains
some overlap, does not necessarily contain all classes of
therapeutic agents useful for the treatment of glaucoma, and is not
necessarily the sole classes of antiglaucoma agents. These types
are: 1. Parasympathomimetics; 2. Sympathomimetics; 3. Alpha
agonists; 4. Beta Blockers; 5. Carbonic anhydrase inhibitors; and
6. Prostaglandin analogs.
[0175] Implants according to embodiments of the present invention
may comprise one or more types of antiglaucoma drugs. In addition
to the 6 types of antiglaucoma drugs listed on the NYGRI website,
other types of antiglaucoma drugs may be utilized in the implants
in alternative embodiments.
[0176] Antiglaucoma drugs have been reviewed, for example, by Ivan
Goldberg in Aust. Preser. 25, 142 (2002), and by S. D. Mathebula in
The South African Optometrist, September, 2005, pages 89-95. The
antiglaucoma drugs that are described in these reviews may be
employed as antiglaucoma drugs in the implants according to
embodiments of the present invention.
[0177] Intraocular pressure reducing agents or antiglaucoma drugs
may reduce the intraocular pressure through various mechanisms.
Although the following discussion generally follows the
classification scheme of the six types of antiglaucoma drugs on the
NYGRI website for convenience, the discussion is illustrative only
and is not meant to be limiting.
[0178] 1. Parasympathomimetics
[0179] Parasympathomimetics, also known as miotics,
cholinomimetrics, or cholinergic agents, may function by opening
the trabecular meshwork and increase the rate of fluid outflow from
the anterior chamber of the eye. Some nonlimiting examples of
parasympathomimetics include pilocarpone, carbachol, and
echothiophate and their derivatives.
[0180] 2. Sympathomimetics
[0181] Sympathomimetics, also known as adrenergic agonists, may
lower the intraocular pressure by increasing the rate of fluid
outflow from the anterior chamber of the eye and may also decrease
the rate of aqueous humor production.
[0182] Epinephrine (adrenaline) may be the most commonly used
sympathomimetic antiglaucoma drug; it is a natural agonist at alpha
2 adrenergic receptors. Dipivefrin is a precursor of epinephrine
and may be converted to epinephrine inside the eye. Dipivefrin may
therefore also be considered to be a sympathomimetic.
[0183] Other sympathomimetrics may also be suitable.
[0184] 3. Alpha Agonists
[0185] Alpha-agonists, particularly those possessing alpha 2
adrenergic receptor activity, may reduce aqueous humor production
and increase aqueous humor outflow. Apraclonidine, clonidine,
p-aminoclonidine, oxymetazoline, epinephrine, norepinephrine, and
cirazoline, dexmedatomidine, mivazerol, xylazine, medatomidine, and
brimonidine are nonlimiting examples of such alpha 2 agonists.
Compounds possessing selective alpha 2 activity, that is a minimum
of alpha 1 agonist activity, are particularly helpful.
[0186] Additionally, newer classes of alpha 2 agonist compounds,
such as those compounds possessing alpha 2B and/or alpha 2C
selective activity, may be particularly useful in providing
antiglaucoma activity without concomitant sedation or
cardiovascular suppression.
[0187] Examples of such compounds, methods of their making, and
methods of screening such compounds are provided, for example and
without limitation, in the following publications, all of which are
incorporated herein by reference in their entirety: U.S. Pat. Nos.
6,329,369; 6,545,182; 6,841,684 and U.S. Patent Publications Serial
No US20020161051, entitled "(2-hydroxy)ethyl-thioureas useful as
modulators of alpha2B adrenergic receptors"; US20030023098,
entitled "Compounds and method of treatment having agonist-like
activity selective at alpha 2B or 2B/2C adrenergic receptors";
US20030092766, entitled "Methods and compositions for modulating
alpha adrenergic receptor activity"; US20040220402, entitled
"4-(substituted cycloalkylmethyl) imidazole-2-thiones,
4-(substituted cycloalkenylmethyl) imidazole-2-thiones,
4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted
cycloalkenylmethyl) imidazol-2-ones and related compounds";
US20040266776, entitled "Methods of preventing and reducing the
severity of stress-associated conditions"; US20050059664 entitled
"Novel methods for identifying improved, non-sedating alpha-2
agonists"; US20050059721, entitled "Nonsedating alpha-2 agonists";
US20050059744 entitled "Methods and compositions for the treatment
of pain and other alpha 2 adrenergic-mediated conditions"; and
US20050075366 entitled
"4-(2-Methyl-5,6,7,8-tetrahydro-quinolin-7-ylmethyl)-1,3-dihydro-imidazol-
e-2-thione as specific alpha2B agonist and methods of using the
same". Additional disclosure concerning non-sedating alpha 2
adrenergic agonists can be found in US20050058696, entitled Methods
and Compositions for the Treatment of Pain and other Alpha 1
Adrenergic Mediated Conditions", and US20040132824, entitled "Novel
Methods and Compositions of Alleviating Pain". All the patents and
patent applications referenced above are incorporated by reference
herein in their entirety.
[0188] These publications show that such non-sedating .alpha.2
receptor agonist compositions contain agents that have already been
characterized in a wide variety of chemical classes, including the
imidazole, thiourea, imidazoline, and imidazole thione,
phenethylamine, amino thiazine, amino imidazoline, benzazepine,
amino oxazoline, amino thiazoline, quinazoline, guanidine,
piperazine, yohimbine alkaloid, and phenoxypropanolamine chemical
classes. It is to be expected that future non-sedating .alpha.2
agents (or combinations of agents) will be found in additional
chemical classes.
[0189] In particular, it has been found that non-sedating .alpha.2
adrenergic agonist compositions have certain biochemical properties
in common, regardless of the chemical structure of the agents
contained in the compositions. For example, in one embodiment such
compounds, in addition to having .alpha.2 adrenergic agonist
activity, particularly but not necessarily exclusively, .alpha.2B
and/or .alpha.2C adrenoreceptor activity, also lack significant al
adrenoreceptor activity. However, in another embodiment, a
therapeutic composition comprising a non-sedating .alpha.2
adrenergic agonist may comprise a combination of an .alpha.2
adrenergic agonist with an al adrenergic antagonist. In each case,
the reduced or absent al adrenergic activity results in a
significant increase in the efficacy of the .alpha.2 adrenergic
agonist activity (reduced EC50 or concentration at which half the
maximum therapeutic effect for that compound is seen) with no
significant increase in the potency of the sedative activity. Thus,
at therapeutically effective concentrations, the .alpha.2
adrenergic agonist has little or no sedative effect, particularly
as compared to a composition comprising an .alpha.2 adrenergic
agonist at a dosage conferring the same therapeutic effect, but
lacking significant OA inhibitory activity.
[0190] Other classes of non-sedating alpha 2 receptor agonists may
include those having alpha 2B and/or alpha 2C agonist activity, but
lacking alpha 2A receptor activity. These compounds have greatly
reduced or absent sedative activity, but retain the neuroprotective
and ocular hypotensive activities characteristic of alpha 2
agonists.
[0191] 4. Beta-Blockers
[0192] Beta-blockers, also known as sympatholytics or adrenergic
antagonists, can decrease the rate at which fluid flows into the
anterior chamber of the eye. According to the Mathebula review,
beta blockers can inhibit aqueous humor formation while leaving the
rate of aqueous humor outflow unchanged.
[0193] Nonlimiting examples of commonly used beta-blockers include
timolol, levobunolol, metipranolol, carteolol, and betaxolol.
[0194] 5. Carbonic Anhydrase Inhibitors
[0195] Carbonic anhydrase inhibitors (CAIs) inhibit the enzyme
carbonic anhydrase. Carbonic anhydrase is an important enzyme in
the body's formation of aqueous humor. Inhibiting the formation of
aqueous humor may reduce the intraocular pressure by better
modulating the rates of aqueous humor inflow and outflow. According
to the Mathebula review, when the intraocular pressure needs to be
lowered quickly, carbonic anhydrase inhibitors may be the drugs of
choice to achieve this purpose.
[0196] Some nonlimiting examples of carbonic anhydrase inhibitors
include dorzolamide, brinzolamide, and dichlorphenamide.
[0197] 6. Prostaglandin Analogs and Derivatives
[0198] Prostaglandin analogs and derivatives may increase
uveoscleral outflow of the aqueous humor. Prostaglandins were
regarded as potent ocular hypertensives for many years; however,
evidence accumulated in the last two decades shows that some
prostaglandins are highly effective ocular hypotensive agents and
are ideally suited for the long-term medical management of
glaucoma. (See, for example, Starr, M. S. EXP. EYE RES. 1971, 11,
pp. 170-177; Bito, L. Z. BIOLOGICAL PROTECTION WITH PROSTAGLANDINS
Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp.
231-252; and Bito, L. Z., APPLIED PHARMACOLOGY IN THE MEDICAL
TREATMENT OF GLAUCOMAS, Drance, S. M. and Neufeld, A. H. eds., New
York, Grune & Stratton, 1984, pp. 477-505). These references
are hereby incorporated by reference in their entirety. Such
prostaglandins include PGF2.alpha., PGF1.alpha., PGE2, and certain
lipid-soluble esters, such as C.sub.1 to C.sub.5 alkyl esters, e.g.
1-isopropyl ester, of such compounds.
[0199] In U.S. Pat. No. 4,599,353 certain prostaglandins, in
particular PGE2 and PGF2.sub..alpha. and the C.sub.1 to C.sub.5
alkyl esters of the latter compound, were reported to possess
ocular hypotensive activity and were recommended for use in
glaucoma management.
[0200] The precise mechanism by which prostaglandins exert their
effects is not yet known. However, while not wishing to be limited
by theory, recent experimental results indicate that the
prostaglandin-induced reduction in intraocular pressure results
from increased uveoscleral outflow [Nilsson et al., INVEST.
OPHTHALMOL. VIS. SCI. 28(suppl), 284 (1987)].
[0201] The isopropyl ester of PGF2.alpha. has been shown to have
significantly greater hypotensive potency than the parent compound,
which was attributed to its more effective penetration through the
cornea. In 1987, this compound was described as "the most potent
ocular hypotensive agent ever reported." [See, for example, Bito,
L. Z., Arch. Ophthalmol. 105, 1036 (1987), and Siebold et al.,
Prodrug 5, 3 (1989)].
[0202] Whereas prostaglandins appear to be devoid of significant
intraocular side effects, ocular surface (conjunctival) hyperemia
and foreign-body sensation have been consistently associated with
the topical ocular use of such compounds, in particular PGF2.alpha.
and its prodrugs, e.g. its 1-isopropyl ester, in humans. The
clinical potential of prostaglandins in the management of
conditions associated with increased ocular pressure, e.g.
glaucoma, has been limited by these side effects.
[0203] Certain prostaglandins and their analogs and derivatives,
such as the PGF2.sub..alpha. derivative latanoprost, sold under the
trademark Xalatan.RTM., have been established as compounds useful
in treating ocular hypertension and glaucoma. However, latanoprost,
the first prostaglandin approved by the United States Food And Drug
Administration for this indication, is a prostaglandin derivative
possessing the undesirable side effect of producing an increase in
brown pigment in the iris of 5-15% of human eyes. The change in
color results from an increased number of melanosomes (pigment
granules) within iridial melanocytes. See e.g., Watson et al.,
OPHTHALMOLOGY 103:126 (1996). While it is still unclear whether
this effect has additional and deleterious clinical ramifications,
from a cosmetic standpoint alone such side effects are usually
undesirable.
[0204] Certain phenyl and phenoxy mono, tri and tetra
prostaglandins and their 1-esters are disclosed in European Patent
Application 0,364,417 as useful in the treatment of glaucoma or
ocular hypertension.
[0205] In a series of United States patent applications assigned to
Allergan, Inc. prostaglandin esters with increased ocular
hypotensive activity accompanied with no or substantially reduced
side-effects are disclosed. U.S. patent application Ser. No.
386,835 (filed Jul. 27, 1989), relates to certain
11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl,
11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF2.alpha..
Intraocular pressure reducing 15-acyl prostaglandins are disclosed
in U.S. Ser. No. 357,394 (filed May 25, 1989). Similarly,
11,15-9,15- and 9,11-diesters of prostaglandins, for example
11,15-dipivaloyl PGF2.alpha. are known to have ocular hypotensive
activity. See U.S. Pat. No. 4,494,274; U.S. patent Ser. No.
584,370, and U.S. Pat. No. 5,034,413; the parent applications were
filed on Jul. 27, 1989.
[0206] Woodward et al U.S. Pat. Nos. 5,688,819 and 6,403,649
disclose certain cyclopentane heptanoic acid, 2-cycloalkyl or
arylalkyl compounds as ocular hypotensives. These compounds, which
can properly be characterized as hypotensive lipids, are effective
in treating ocular hypertension.
[0207] As one example, the prostamide, bimatoprost, has been
discovered to be effective in reducing intraocular pressure
possibly by increasing the aqueous humour outflow of an eye
(Woodward et al., AGN 2024 (Lumigan.RTM.): A Synthetic Prostamide
Analog that Lowers Primate Intraocular Pressure by Virtue of Its
Inherent Pharmacological Activity, ARVO 2002; (CD-ROM):POS; Chen et
al., Lumigan.RTM.: A Novel Drug for Glaucoma Therapy, OPTOM IN
PRACT, 3:95-102 (2002); Coleman et al., A 3-Month Randomized
Controlled Trial of Bimatoprost (LUMIGAN) versus Combined Timolol
and Dorzolamide (Cosopt) in Patients with Glaucoma or Ocular
Hypertension, OPHTHALMOLOGY 110(12): 2362-8 (2003); Brubaker,
Mechanism of Action of Bimatoprost (Lumigan.TM.), SURV OPHTHALMOL
45 (Suppl 4):5347-5351 (2001); and Woodward et al., The
Pharmacology of Bimatoprost (Lumigan.TM.), SURV OPHTHALMOL 45
(Suppl 4) S337-S345 (2001).
[0208] Bimatoprost is a structural derivative of a naturally
occurring prostamide. Bimatoprost's chemical name is
(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[1E,3S)-3-hydroxy-5-phenyl-1-penteny-
l]cyclopentyl]-5-N-ethylheptenamide, and it has a molecular weight
of 415.58. Its molecular formula is C.sub.25H.sub.37NO.sub.4.
Bimatoprost is available in a topical ophthalmic solution under the
tradename Lumigan.RTM. (Allergan, Inc.). Each mL of the solution
contains 0.3 mg of bimatoprost as the active agent, 0.05 mg of
benzalkonium chloride (BAK) as a preservative, and sodium chloride,
sodium phosphate, dibasic; citric acid; and purified water as
inactive agents.
[0209] In addition to latanoprost and bimatoprost, unoprostone is
another example of a currently marketed prostaglandin inhibitors.
Other prostaglandin inhibitors may be utilized in alternative
embodiments.
[0210] Combinations of antiglaucoma drugs or intraocular pressure
reducing agents may also be used in embodiments of the present
invention.
[0211] It is commonly thought that drug combinations that act on
different receptor sites or enzymes and that have different modes
of action are preferred. Table 3 of the Mathebula reference
provides a matrix of classes of antiglaucoma drugs showing some
classes of antiglaucoma drugs that can have an additive or
synergistic effect on one another compared to the use of a single
class of antiglaucoma drugs.
[0212] As an example, beta blockers, which lower aqueous humor
production, can be combined with miotics, which enhance aqueous
trabecular outflow.
[0213] As another example, the beta blocker betaxolol can be
combined with the sympathomimetics epinephrine or dipivefrin. The
combination results in a significant reduction in intraocular
pressure due to increased outflow of fluid from the eye.
[0214] Timolol may be used in combination with dorzolamide,
brimonidine or latanoprost. Other combinations of antiglaucoma
drugs may be utilized in other embodiments.
[0215] In an embodiment of the present invention, an ocular implant
can comprise a steroid and an auxiliary agent, wherein said
auxiliary agent comprises an antiglaucoma drug.
[0216] In another embodiment, a first ocular implant can comprise a
steroid, and a second ocular implant can comprise an auxiliary
agent comprising an antiglaucoma drug.
[0217] In yet another embodiment, mixtures of implants may be
utilized, where the mixture of implants may be selected from the
group consisting of an implant that comprises a steroid, an implant
that comprises an antiglaucoma drug, an implant that comprises a
mixture of a steroid and an antiglaucoma drug, and mixtures
thereof.
[0218] The steroid may, without limitation, be selected from the
group consisting of dexamethasone, fluocinolone, fluocinolone
acetonide, triamcinolone, triamcinolone acetonide, beclomethasone,
beclamethasone diproprionate, and mixtures thereof. Other steroids
may be utilized in other embodiments.
[0219] It will be understood that the antiglaucoma drugs discussed
herein comprise a specific example of an auxiliary agent.
[0220] In this embodiment of the invention the antiglaucoma drug
(auxiliary agent) may, without limitation, be selected from the
group consisting of a parasympathomimetic, a sympathomimetic, an
alpha agonist, a beta blocker, a carbonic anhydrase inhibitor, a
prostaglandin analog, an ocular neuroprotectant, and mixtures
thereof. Other types of antiglaucoma drugs may be utilized in other
embodiments.
[0221] The antiglaucoma drug may, without limitation, also be
selected from the group consisting of pilocarpone, carbachol,
echothiophate, epinephrine, dipivefrin, apracionidine, timolol,
levobunolol, metipranilol, carteolol, betaxolol, dorzolamine,
brinzolamide, dichlorphenamide, latanoprost, bimatoprost,
unoprostone, apraclonidine, clonidine, p-aminoclonidine,
oxymetazoline, norepinephrine, cirazoline, dexmedatomidine,
mivazerol, xylazine, medatomidine, and brimonidine and mixtures
thereof. Other antiglaucoma drugs may also be suitable.
[0222] The ocular implants according to these embodiments of the
present invention may comprise any of the polymeric matrices,
geometric configurations, or other embodiments of implants that
were previously described for ocular implants that comprise
steroids.
[0223] In some embodiments, an implant that comprises a steroid and
an antiglaucoma drug may comprise a first polymeric matrix that may
be associated with the steroid and a second polymeric matrix that
may be associated with the antiglaucoma drug. The first polymeric
matrix may be the same as the second polymeric matrix, or the first
polymeric matrix may be different than the second polymeric
matrix.
[0224] Similarly, in an embodiment where a first implant comprises
a steroid, and a second implant comprises an antiglaucoma drug, the
first implant and the second implant may comprise the same
polymeric matrix, or the first implant and the second implant may
comprise different polymeric matrices.
[0225] The rate of release and the timing of release of the steroid
and the antiglaucoma drug from the implant or implants may be
optimized, for example, by adjusting the amounts and types of the
polymeric formulations that form the polymeric matrices of the
implant or implants.
[0226] In some embodiments, the implant comprising the steroid, the
antiglaucoma drug, or both the steroid and the antiglaucoma drug
may comprise at least one layer or coating covering a core region
of the implant. In some embodiments, the covering may comprise a
plurality of openings or holes through which the steroid, the
antiglaucoma drug, or both the steroid and the antiglaucoma drug
may pass to an external environment, for example to the ocular
region of the eye.
[0227] The properties of the coating and the size or number of
openings or holes in the coating may be adjusted to provide optimum
delivery of the steroid and antiglaucoma drug.
[0228] The timing and the duration of release of the steroid and
antiglaucoma drug may therefore be adjusted, for example, by
changing the formulation of the polymeric matrix and/or the
configuration of the implant or implants.
[0229] In some embodiments, the steroid may be released from the
implant or implants simultaneously with the release of the
antiglaucoma drug from the implant.
[0230] In other embodiments, the antiglaucoma drug may be released
from the implant or implants at a different time than a time when
the steroid is released.
[0231] For example, in some embodiments, the antiglaucoma drug may
be released from the implant or implants before the steroid is
released. In other embodiments, the antiglaucoma drug may be
released from the implant or implants after the steroid is
released.
[0232] In still other embodiment, the release of the steroid may be
pulsed or otherwise varied while the antiglaucoma drug is delivered
at a substantially constant rate by comparison over the same time
period.
[0233] The relative effectiveness of releasing the steroid and
antiglaucoma drug simultaneously or at different times may depend
on the steroid, the antiglaucoma drug, the patient, the formulation
of the polymeric matrix of the implant, the configuration of the
implant, or many other factors.
[0234] In an embodiment in which the antiglaucoma drug is released
from the implant before the steroid is released from the implant,
the antiglaucoma drug that is already present when the steroid is
released may sometimes be more effective in counteracting any
increase in intraocular pressure that may be induced by the release
of the steroid than if the antiglaucoma drug were released after
the steroid is released.
[0235] In an alternative embodiment in which the antiglaucoma drug
is released from the implant at a later time than the steroid, some
antiglaucoma drugs may be effective at rapidly reducing the
increase in intraocular pressure that may be caused by the prior
release of the steroid from the implant. For example, as previously
discussed, carbonic anhydrase inhibitors can rapidly reduce the
intraocular pressure. Releasing a carbonic anhydrase inhibitor
antiglaucoma drug after releasing the steroid may sometimes be an
effective treatment for ocular diseases.
[0236] The steroid and the antiglaucoma drug may also be released
from the implant or implants continuously or intermittently.
Continuous or intermittent release of the steroid and the
antiglaucoma drug may both be effective.
[0237] For example, if the steroid and the antiglaucoma drug are
released continuously, the continuous release of the antiglaucoma
drug may mitigate any increase in the intraocular pressure that may
be caused by the continuous release of the steroid.
[0238] In an embodiment in which the steroid and the antiglaucoma
drug may be released intermittently, halting the release of the
steroid may allow the intraocular pressure in the eye to decline to
a lower pressure. Releasing the antiglaucoma drug from the implant
after the ocular pressure has declined somewhat after the release
of the steroid has been halted may sometimes enhance the
effectiveness of the antiglaucoma drug in lowering the ocular
pressure in the eye.
[0239] In another embodiment, the steroid may be released from the
implant continuously, and the antiglaucoma drug may be released
intermittently. An intermittent release of the antiglaucoma drug
may optimize the reduction of the intraocular pressure that may
have been increased by the release of the steroid.
[0240] In some embodiments, the steroid and the antiglaucoma drug
may be released alternately. For example, a pulse of steroid may be
followed by a pulse of antiglaucoma drug, followed in turn by
another pulse of steroid.
[0241] In some instances, the concentration of steroid in the
vitreous fluid may be at a higher level when an implant comprising
steroid is first contacted with the vitreous fluid in the eye than
at later times. The "spike" in the concentration of steroid in the
vitreous fluid when the implant is first introduced into the eye
could potentially lead to a corresponding spike in the ocular
pressure in the eye. The spike in ocular pressure may increase the
likelihood that a patient could develop glaucoma. It may therefore
be advantageous to avoid high levels of steroid in the vitreous
fluid of the patient when the implant is introduced into the eye of
the patient.
[0242] Further, a patient may be more likely to develop glaucoma if
the vitreous fluid of the patient continuously contains steroid for
an extended period of time than if the vitreous fluid contains high
levels of steroid for only a short period of time. The time that
the steroid may be present in the vitreous fluid in the eye of the
patient continuously without having the patient having an increased
risk of developing glaucoma may vary from patient to patient.
Generally, exposing the vitreous fluid in an eye of a patient to
steroid continuously for approximately six months or more may lead
to increased rates of glaucoma. It may therefore be advantageous to
avoid continuously releasing steroid into the vitreous fluid for
extended periods of time of, for example, six months or more.
[0243] The relative timing and the length of time of release of the
steroid and the antiglaucoma drug may be varied, for example, by
varying the formulation of the polymeric matrix and/or the
configuration of the implant or implants. The following examples
are illustrative only and are not meant to be limiting.
[0244] For example, the implant may comprise a first polymeric
formulation associated with a steroid, where the first polymeric
formulation may release the steroid at a relatively rapid rate. The
implant may also comprise a second polymeric formulation that is
associated with an antiglaucoma drug, where the second polymeric
formulation may release the antiglaucoma drug at a slower rate than
the rate at which the steroid is released from the first polymeric
formulation. The slower rate of release of the antiglaucoma drug
from the second polymeric formulation may provide a longer period
of time of protection in which the intraocular pressure may be
lowered by the presence of the antiglaucoma drug.
[0245] In another embodiment, the implant may comprise a steroid in
an exterior portion of the polymeric formulation and an
antiglaucoma drug in an interior portion of the polymeric
formulation. The steroid in the exterior portion of the polymer may
be released quickly, and the antiglaucoma drug on the interior
portion of the polymer may be released at a later time. Releasing
the antiglaucoma drug after the steroid is released may aid in
lowering any increase in intraocular pressure due to release of the
steroid.
[0246] The implant may be configured to release steroid and
antiglaucoma drug alternately in different ways. For example, an
ocular implant may comprise alternating layers of steroid and
antiglaucoma drug such that the steroid and the antiglaucoma drug
may be released from the implant on an alternating basis.
[0247] The polymeric formulation or configuration of the implant
comprising steroid may also be designed to avoid high initial
levels of steroid in the vitreous fluid. For example, the polymer
of the implant may be designed to have small pores. The small pores
may slow the release of the steroid from the implant, mitigating
the "spike" in the initial steroid concentration. In an alternative
embodiment, the implant may comprise an impermeable coating having
a plurality of holes in the coating, where the size of the
plurality of holes may be relatively small. Other ways to avoid
high initial levels of steroid will be apparent to those skilled in
the art.
[0248] The manner and timing of the release of the steroid and the
antiglaucoma drug (or auxiliary agent) may therefore be optimized
by changing the formulation of the polymeric matrix and/or the
configuration of the implant or implants. The optimal
configurations and formulations for the implant or implants may
depend on the quantities and types of the steroid and the
antiglaucoma drug.
[0249] A method for treating ocular diseases in a patient comprises
contacting an implant comprising a steroid and an implant
comprising an antiglaucoma drug with the vitreous fluid in the eye
of the patient. The implant comprising the antiglaucoma drug may be
the same or different than the implant comprising the steroid.
Contacting the implant comprising the steroid with the vitreous
fluid may release a therapeutic amount of steroid into the vitreous
fluid. Contacting the implant comprising the antiglaucoma drug with
the vitreous fluid may release a therapeutic amount of antiglaucoma
drug into the vitreous fluid.
[0250] Releasing the steroid into the vitreous fluid may sometimes
increase the intraocular pressure in the eye of the patient. An
increase in the intraocular pressure could increase the likelihood
of the patient developing complications such as glaucoma.
[0251] Releasing antiglaucoma drug into the vitreous fluid from the
implant comprising the antiglaucoma drug may lessen any increase in
intraocular pressure that may be caused by releasing the steroid
into the vitreous fluid.
[0252] The method may further comprise providing implants or
mixtures of implants having configurations and formulations as
previously described.
EXAMPLES
[0253] The following non-limiting examples provide those of
ordinary skill in the art with specific preferred drug delivery
systems, methods of making such systems, and methods to treat
conditions within the scope of the present invention. The following
examples are not intended to limit the scope of the invention.
Example 1
Manufacture and Testing of Implants Containing Flucinolone and a
Biodegradable Polymer Matrix
[0254] Fluocinolone acetonide was combined with a polymer in a
stainless steel mortar and mixed using the Turbula shaker set at 96
RPM for 15 minutes. The powder of the fluocinolone and polymer was
scraped off the walls of the steel mortar and then mixed again for
an additional 15 minutes. The powder blend was heated at
temperatures ranging from 110.degree. C. to 160.degree. C.,
depending on the polymer used, for a total of 30 minutes, forming a
polymer/drug melt. The melt was pelletized, then loaded into the
barrel and extruded into filaments, and finally the filaments were
cut into about 0.5 mg or about 1 mg size implants. The implants had
a weight range from about 450 .mu.g to about 550 .mu.g, or from
about 900 .mu.g to about 1100 .mu.g. The 1 mg size implants had a
length of about 2 mm and a diameter of about 0.72 mm.
[0255] Each implant was placed in a 20 ml screw cap vial with 10 ml
of 0.9% saline. The vials were placed in a shaking water bath at
37.degree. C. 9 ml aliquots were removed and replaced with equal
volume of fresh media on day 1, 4, 7 and every week thereafter. The
in-vitro release testing was performed on each lot of implants in
six replicates.
[0256] The drug assays were performed by HPLC, consisting of a
Waters 2690 Separation Module (or 2696) and Waters 2996 Photodiode
Array Detector. A Varian Microsorb-MV.TM. 100 .ANG. C18 column was
used for separation and the detector was set at 254 nm. The mobile
phase was (50:50) acetonitrile/0.005M sodium acetate (pH=4.0). The
flow rate was 1.00 ml/min and the total run time for was 6 minutes.
The release rate was determined by calculating the amount of drug
released in a given volume of medium over time in .mu.g/day.
[0257] A total of 20 fluocinolone acetonide formulations were
prepared, as shown in Table 1. The polymers used were Boehringer
Ingelheim Resomers RG755, RG503, R202H, RG502H, and RG502. The
inherent viscosities were about 0.6, 0.4, 0.2, 0.2, and 0.2 dl/g,
respectively. The average molecular weights were 40000, 28300,
6500, 8400, and 11400 daltons, respectively.
TABLE-US-00001 TABLE 1 Fluocinolone Acetonide Formulations
Formulation Lot FA (w/w) Polymer I.V. (dl/g) Melt T Extru T (core)
Nozzle DDS Size 1 453-98A 40% RG755 0.6 160.degree. C. 122.degree.
C. 380 .mu.m 0.5 mg 2 453-98B 40% RG755 0.6 160.degree. C.
122.degree. C. 720 .mu.m 0.5 mg 3 453-99 20% RG755 0.6 160.degree.
C. 116.degree. C. 720 .mu.m 1 mg 4 453-100 40% RG503 0.4
150.degree. C. 116.degree. C. 720 .mu.m 0.5 mg 5 453-101 20% RG503
0.4 150.degree. C. 106.degree. C. 720 .mu.m 1 mg 6 453-116 40%
R202H 0.2 110.degree. C. 90.degree. C. 720 .mu.m 0.5 mg 7 453-117
40% RG752 0.2 110.degree. C. 90.degree. C. 720 .mu.m 0.5 mg 8
453-118 40% RG502H 0.2 110.degree. C. 84.degree. C. 720 .mu.m 0.5
mg 9 453-119 40% RG502 0.2 110.degree. C. 92.degree. C. 720 .mu.m
0.5 mg 10 453-120 40% (1:1) RG502H/R202H 0.2 110.degree. C.
85.degree. C. 720 .mu.m 0.5 mg 11 453-121 40% (1:1) RG502H/RG752
0.2 110.degree. C. 83.degree. C. 720 .mu.m 0.5 mg 12 453-128 60%
(3:1) RG502H/R202H 0.2 110.degree. C. 95.degree. C. 720 .mu.m 0.5
mg 13 453-129 60% (3:1) RG502H/RG752 0.2 110.degree. C. 101.degree.
C. 720 .mu.m 0.5 mg 14 453-130 60% (3:1) RG502H/RG502 0.2
110.degree. C. 101.degree. C. 720 .mu.m 0.5 mg 15 453-131 60% (1:1)
RG502H/R202H 0.2 110.degree. C. 101.degree. C. 720 .mu.m 0.5 mg 16
453-137 40% (1:2) RG502H/R202H 0.2 110.degree. C. 88.degree. C. 720
.mu.m 1 mg 17 453-138 40% (1:2) RG502H/RG752 0.2 110.degree. C.
85.degree. C. 720 .mu.m 1 mg 18 453-139 40% (1:2) RG502H/RG502 0.2
120.degree. C. 85.degree. C. 720 .mu.m 1 mg 19 453-140 40% (1:2)
RG502H/RG503 n.a. 120.degree. C. 99.degree. C. 720 .mu.m 1 mg 20
453-141 40% (1:2) RG502H/RG755 n.a. 120.degree. C. 99.degree. C.
720 .mu.m 1 mg FA = Fluocinolone Acetonide I.V. = inherent
viscosity Melt T = melting temperature Extru T = extrusion
temperature Nozzle = nozzle diameter (.mu.m) DDS size = drug
delivery system size (i.e., the weight of an individual
implant)
[0258] Of the 20 formulations prepared, 16 were screened for
release testing (formulations #1-11 and 16-20). Initially, the
release medium was 10 mL phosphate buffer-saline (PBS) with 1 mL
replacement at each time point, but almost no release was observed
up to three weeks. The release medium was subsequently changed to
PBS with 9 mL replacement, but the release was inconsistent and
with unacceptably high standard deviations. Finally, the release
medium was switched to 0.9% saline with 9 mL replacement at each
time point. The release profiles are shown in FIGS. 1 and 2.
[0259] Most of the fluocinolone acetonide formulations released the
total drug load in approximately 2-3 months. Of the 16
formulations, 11 formulations exhibited release for about two
months. Of the 11 formulations, 6 formulations exhibited release
for about three months.
[0260] In particular, all formulations prepared with Resomer RG755
(453-98A, 453-98B, and 453-99) and RG752 (453-117) showed almost no
release after day 4 and their release studies were stopped after 1
month.
[0261] Formulations prepared with RG503 (453-100 and 453-101) and
RG502 (453-119) showed a delay of 3-4 weeks before releasing 100%
between day 49 and day 56.
[0262] The formulation prepared with RG502H (453-118) appeared to
be the fastest, on day 49.
[0263] The formulation prepared with a (1:1) mixture of RG502H and
R202H led to the longest release, up to 84 days.
[0264] Finally, the formulation prepared with a (1:1) mixture of
RG502H and RG752 appeared to be slower than the one prepared with
RG502H (453-118) at first, but eventually ended up having complete
release at day 49.
[0265] Based on these data, it was concluded that a mixture of
RG502H and other polymers with slower release will provide a
formulation with longer release and relatively closer to zero-order
kinetics. One formulation with desirable release properties was a
1:2 mixture of RG502H and R202H, which led to a release of 94% of
the fluocinolone after 84 days.
Example 2
Manufacture and Testing of Implants Containing Triamcinolone and a
Biodegradable Polymer Matrix
[0266] Triamcinolone acetonide was combined with a polymer in a
stainless steel mortar and mixed using the Turbula shaker set at 96
RPM for 15 minutes. The powder of the fluocinolone and polymer was
scraped off the walls of the steel mortar and then mixed again for
an additional 15 minutes. The powder blend was heated at
temperatures ranging from 110.degree. C. to 160.degree. C.,
depending on the polymer used, for a total of 30 minutes, forming a
polymer/drug melt. The melt was pelletized, then loaded into the
barrel and extruded into filaments, and finally the filaments were
cut into about 0.5 mg or about 1 mg size implants. The implants had
a weight range from about 450 .mu.g to about 550 .mu.g, or from
about 900 .mu.g to about 1100 .mu.g. The 1 mg size implants had a
length of about 2 mm and a diameter of about 0.72 mm.
[0267] The testing of the triamcinolone implants was performed as
described in Example 1.
[0268] A total of 16 triamcinolone acetonide formulations were
prepared, as shown in Table 2. The polymers used were Boehringer
Ingelheim Resomers RG755, RG503, R202H, RG502H, and RG502. The
inherent viscosities were 0.6, 0.4, 0.2, 0.2, and 0.2 dl/g,
respectively. The average molecular weights were 40000, 28300,
6500, 8400, and 11400 daltons, respectively.
TABLE-US-00002 TABLE 2 Triamcinolone Acetonide Formulations
Formulation Lot TA (w/w) Polymer I.V. (dl/g) Melt T Extru T (core)
Nozzle DDS Size 1 453-96 50% RG755 0.6 160.degree. C. 122.degree.
C. 720 .mu.m 1 mg 2 453-97 50% RG503 0.4 150.degree. C. 116.degree.
C. 720 .mu.m 1 mg 3 453-112 50% RG502 0.2 110.degree. C.
105.degree. C. 720 .mu.m 1 mg 4 453-113 50% RG502H 0.2 110.degree.
C. 90.degree. C. 720 .mu.m 1 mg 5 453-114 50% RG752 0.2 110.degree.
C. 95.degree. C. 720 .mu.m 1 mg 6 453-115 50% R202H 0.2 110.degree.
C. 96.degree. C. 720 .mu.m 1 mg 7 453-122 50% (1:1) RG502H/RG752
0.2 110.degree. C. 83.degree. C. 720 .mu.m 1 mg 8 453-123 50% (1:1)
RG502H/R202H 0.2 110.degree. C. 85.degree. C. 720 .mu.m 1 mg 9
453-125 60% (3:1) RG502H/RG502 0.2 110.degree. C. 92.degree. C. 720
.mu.m 1 mg 10 453-126 60% (3:1) RG502H/R202H 0.2 110.degree. C.
92.degree. C. 720 .mu.m 1 mg 11 453-127 60% (3:1) RG502H/RG752 0.2
110.degree. C. 95.degree. C. 720 .mu.m 1 mg 12 453-132 60% (1:1)
RG502H/R202H 0.2 110.degree. C. 108.degree. C. 720 .mu.m 1 mg 13
453-133 50% (1:1) RG502H/RG502 0.2 110.degree. C. 99.degree. C. 720
.mu.m 1 mg 14 453-134 50% (1:1) RG502H/RG755 N/A 110.degree. C.
110.degree. C. 720 .mu.m 1 mg 15 453-135 50% (1:1) RG502H/RG503 N/A
110.degree. C. 110.degree. C. 720 .mu.m 1 mg 16 453-136 50% (3:1)
RG502H/RG502 0.2 110.degree. C. 88.degree. C. 720 .mu.m 1 mg TA =
Triamcinolone Acetonide I.V. = inherent viscosity Melt T = melting
temperature Extru T = extrusion temperature Nozzle = nozzle
diameter (.mu.m) DDS size = drug delivery system size (i.e., the
weight of an individual implant)
[0269] Of the 16 formulations prepared, 8 were screened for release
testing (formulations #1-8). The same problem was encountered with
the release medium as that of fluocinolone. The release medium was
switched to 0.9% saline with 9 mL replacement at each time point.
The release profiles are shown in FIG. 3.
[0270] Certain triamcinolone acetonide formulations had release
periods of about 4-6 months. Of the eight formulations, five
formulations exhibited 4 or more months of release, and two
formulations exhibited release for more than 5 months.
[0271] Formulations prepared with RG755 (453-96), RG752 (453-114)
and R202H (453-115) showed essentially zero to very slow
release.
[0272] The formulation prepared with RG502H (453-113) had the
fastest and perhaps smoothest release profile with minimal delay
lasting close to 4 months.
[0273] The formulation prepared with RG502 (453-112) showed an
equally fast release of 4 months, but there was a 2-3 weeks lag
time.
[0274] The formulation prepared with RG503 (453-97) showed a
release longer than 4 months, but it also had 4 weeks lag time.
[0275] Similar to the formulations in Example 1, the formulation
prepared with a (1:1) mixture of RG502H and R202H lot (453-123) led
to a desirable release profile approaching 5 to 6 months. This
release profile was the most linear and the longest (>140
days).
[0276] Based on the data of Examples 1 and 2, polymer blends
appeared to achieve a more desired controlled release rate relative
to single polymers. Using a slow degrading poly(D.L-lactide), such
as R202H, and mixing it with a fast degrading
poly(D,L-lactide-co-glycolide), such as RG502H, is effective in
controlling the release rate of both fluocinolone and triamcinolone
acetonide.
Example 3
Manufacture and In Vitro Testing of Implants Containing
Fluocinolone and a Polymeric Coating
[0277] Silicone tubing (Specialty Silicone Fabricators, Inc,
SSF-METN-755, P.N. OP-2) was cut to either 10 mm or 7 mm tubes to
form an implant element. Holes of various sizes were drilled
(Photomachining, Inc) in the cut tubes. The configuration of each
tube was characterized by the number of holes, the diameter of
holes and the distance between the holes, as well as the tube
length and the sterility of the tube. Each drilled tube was glued
on one end with silicone adhesive (Nusil Silicone Technology,
MED-1511), and dried for 72 hours at ambient temperature and then
packed with fluocinolone acetonide. Each of the 10 mm long tube
contained 4 to 5 mg of fluocinolone, while each of the 7 mm long
tubes contained 2 to 3 mg of fluocinolone. Finally, the other end
of each tube was glued and dried for 72 hours. The implants did not
include any additional excipients or release modifiers. A total of
30 different tube configurations were tested and are described in
Table 3.
TABLE-US-00003 TABLE 3 Fluocinolone Reservoir Delivery Technology
Configurations Average Before or After Tube Number of Configuration
Lot # # Hole/Diam/Distance Drug Load (.mu.g) .gamma. Sterilization
Length Replicates 1 257-172-1 2 hole - 250 .mu.m - 2 mm 4526 (n =
3) BS 1 cm 3 2 257-172-4 2 hole - 500 .mu.m - 2 mm 4667 (n = 3) BS
1 cm 3 3 257-172-7 3 hole - 250 .mu.m - 2 mm 4508 (n = 3) BS 1 cm 3
4 257-172-10 3 hole - 500 .mu.m - 2 mm 4437 (n = 3) BS 1 cm 3 5
267-33-1 2 hole - 250 .mu.m - 2 mm 4699 (n = 1) AS 1 cm 1 6
267-33-2 3 hole - 250 .mu.m - 2 mm 4536 (n = 1) AS 1 cm 1 7
267-33-3 2 hole - 500 .mu.m - 2 mm 4457 (n = 1) AS 1 cm 1 8
267-33-4 3 hole - 500 .mu.m - 2 mm 4214 (n = 1) AS 1 cm 1 9 267-140
2 hole - 375 .mu.m - 2 mm 5228 (n = 3) BS 1 cm 3 10 267-140 2 hole
- 460 .mu.m - 2 mm 4466 (n = 3) BS 1 cm 3 11 267-140 3 hole - 325
.mu.m - 2 mm 4867 (n = 3) BS 1 cm 3 12 267-140 3 hole - 375 .mu.m -
2 mm 4566 (n = 3) BS 1 cm 3 13 285-1AS 2 hole - 375 .mu.m - 2 mm
4663 (n = 3) AS 1 cm 3 14 285-1AS 2 hole - 460 .mu.m - 2 mm 4806 (n
= 3) AS 1 cm 3 15 285-1AS 3 hole - 325 .mu.m - 2 mm 5168 (n = 3) AS
1 cm 3 16 285-1AS 3 hole - 375 .mu.m - 2 mm 4981 (n = 3) AS 1 cm 3
17 285-54 2 hole - 250 .mu.m - 2 mm 2804 (n = 3) AS 0.7 cm 3 18
285-54 2 hole - 500 .mu.m - 2 mm 2428 (n = 3) AS 0.7 cm 3 19 285-54
3 hole - 375 .mu.m - 2 mm 3068 (n = 3) AS 0.7 cm 3 20 285-54 3 hole
- 500 .mu.m - 2 mm 2899 (n = 3) AS 0.7 cm 3 21 285-126C 2 hole -
250 .mu.m - 1 mm 2770 (n = 3) BS 0.7 cm 3 22 285-126C 2 hole - 375
.mu.m - 1 mm 2591 (n = 3) BS 0.7 cm 3 23 285-126C 2 hole - 375
.mu.m - 2 mm 3245 (n = 3) BS 0.7 cm 3 24 285-126C 2 hole - 500
.mu.m - 1 mm 2819 (n = 3) BS 0.7 cm 3 25 285-126C 3 hole - 500
.mu.m - 1.5 mm 2955 (n = 3) BS 0.7 cm 3 26 285-126D 2 hole - 250
.mu.m - 1 mm 2615 (n = 3) AS 0.7 cm 3 27 285-126D 2 hole - 375
.mu.m - 1 mm 2970 (n = 3) AS 0.7 cm 3 28 285-126D 2 hole - 375
.mu.m - 2 mm 2932 (n = 3) AS 0.7 cm 3 29 285-126D 2 hole - 500
.mu.m - 1 mm 2619 (n = 3) AS 0.7 cm 3 30 285-126D 3 hole - 500
.mu.m - 1.5 mm 2498 (n = 3) AS 0.7 cm 3
[0278] Each of the 30 implants was placed into a 5 mL centrifuge
vial with cap containing 1 mL of phosphate buffer-saline, pH 7.4
(PBS) at 37.degree. C. Total replacement with equal volume of fresh
medium was performed on day 1, 4, 7, 14, 28, and every week
thereafter. Drug assay was performed on a Waters HPLC system, which
included a 2690 (or 2696) Separation Module, and a 2996 Photodiode
Array Detector. A Rainin C18, 4.6.times.100 mm column was used for
separation and detector was set at 254 nm. The mobile phase was
(50:50) acetonitrile-0.005M NaOAc/HOAc, pH 4.0 with flow rate of 1
mL/min and a total run time of 10 min per sample. Release rates
were determined by calculating the amount of drug being released in
a given volume of medium over time and expressed in .mu.g/day. The
release testing was performed on all 30 configurations in three
replicates, except for configurations #5 to 8, for which only one
sample of each was tested.
[0279] The implants studied varied in the number of holes (2 or 3),
hole sizes (250, 325, 375, 460, or 500 .mu.m), distance between the
holes (1 mm, 1.5 mm, or 2 mm), length of the implant (1 cm or 0.7
cm), and before or after gamma sterilization, as presented in Table
3.
[0280] In general, all 30 implants exhibited an initial burst of
drug release on the first day then tapered off to day 7 or later,
and finally gradually settled into an equilibrium release range
starting after day 14. The first eight configurations were 1 cm in
length with drug load of approximately 4.5 mg.+-.0.2 mg in each
device, as shown in Table 3. Configurations 1 through 4 were
non-sterile, while configurations 5 through 8 were sterile. The
cumulative amount released (.mu.g) as a function of time and the
amount of release (.mu.g) per day as a function of time are
presented in FIGS. 4 through 7.
[0281] Configuration #1 (2 hole--250 .mu.m), #2 (2 hole--500
.mu.m), #3 (3 hole--250 .mu.m), and #4 (3 hole--500 .mu.m) gave an
average release of 0.63.+-.0.23, 1.72.+-.0.52, 0.94.+-.0.30, and
2.82 .mu.g/day.+-.0.41 .mu.g/day, respectively from day 14 to day
487. These results were compared to their sterile counterparts,
configuration #5, #6, #7, and #8, which gave an average release of
0.88, 1.10, 2.48, and 2.84 .mu.g/day, respectively from day 14 to
day 448. A good correlation between the number of holes in a
configuration and its average daily release was observed for the
first four configurations. For example, configuration #3 has 3
holes and configuration #1 has two holes of the same diameter as
#3, and configuration #3 released 11/2 times more fluocinolone per
day than configuration #1. Similar results were obtained with
configuration #4 and configuration #2.
[0282] In configuration #5 (2 hole--250 .mu.m), #6 (2 hole--500
.mu.m), #7 (3 hole--250 .mu.m), and #8 (3 hole--500 .mu.m), we see
approximately a three fold increase in the release rates between
configuration #7 and #5, and also between configuration #8 and #6.
This was a two-fold increase comparing to the non-sterile
counterparts. Configuration #5 (2 holes--250 .mu.m) released an
average of 1 .mu.g/day, and configuration #7 (2 holes--500 .mu.m)
released an average of 3 .mu.g/day.
[0283] Configurations #9 (2 hole--375 .mu.m), #10 (2 hole--460
.mu.m), #11 (3 hole--325 .mu.m), and #12 (3 hole--375 .mu.m) were
made and were non-sterile, while configurations 13 through 16 were
the sterile counterparts. The cumulative amount released (.mu.g) as
a function of time and the amount of release (.mu.g) per day as a
function of time are presented in FIGS. 8 through 11. Results from
day 14 to day 397 showed an average release of 1.02.+-.0.25,
1.22.+-.0.29, 1.06.+-.0.21, and 1.50.+-.0.39 .mu.g/day for
configurations 9, 10, 11, and 12, respectively. Similarly, the data
for configurations 13, 14, 15, and 16, which were the sterile
counterparts, showed an average release of 1.92.+-.0.23,
2.29.+-.0.33, 1.94.+-.0.18, and 3.15.+-.0.64 .mu.g/day,
respectively. Each of the sterile configurations appeared to be
releasing twice as fast as its non-sterile counterpart.
[0284] Configuration #13 (2 hole--375 .mu.m-2 mm apart) exhibited
an average release of 1.92.+-.0.23 .mu.g/day from day 14 through
day 376. Likewise, configuration #15 (3 hole--325 .mu.m-2 mm apart)
achieved an average release of 1.94.+-.0.18 .mu.g/day from day 14
through day 376. In the same period of time, configurations #14 and
#16 achieved an average release of 2.29 .mu.g.+-.0.33 .mu.g/day and
3.15 .mu.g.+-.0.64 .mu.g/day, respectively. Furthermore,
configurations #13 and #15 achieved a total release of
16.02%.+-.0.78% and 14.22%.+-.1.13%, respectively, after 376 days.
Based on the release rate, the predicted life span of
configurations #13 and #15 are 6.4 and 7.24 years,
respectively.
[0285] Implants were also manufactured to provide a fluocinolone
release rate of about 0.5 .mu.g/day. Tubular implants were
manufactured to have a length of about 0.7 cm filled with
approximately 2.8 mg.+-.0.34 mg of drug and are identified as
configurations 17, 18, 19, and 20. The cumulative amount of
fluocinolone released (.mu.g) as a function of time and the amount
of release (.mu.g) per day as a function of time are presented in
FIGS. 12 and 13, respectively.
[0286] The results showed an average release of 0.95.+-.0.14,
1.71.+-.0.55, 1.93.+-.0.56, and 2.76.+-.0.27 .mu.g/day, for
configurations 17, 18, 19, and 20, respectively, from day 14
through day 329. Since the length of the tube for configurations
17, 18, 19, and 20 was shortened from 1.0 cm to 0.7 cm,
approximately 0.15 cm of silicone tubing was removed from both
ends. As a result, the holes became much closer to the end of the
tube, to the extent that the glue almost touched the circumference
of the holes during preparation. It was not clear whether this
affected the release profiles. To circumvent this potential
problem, configurations with holes much closer to each other toward
the center and away from the ends were prepared.
[0287] The last ten configurations were 0.7 cm in length with drug
load of approximately 2.69 mg.+-.0.36 mg in each device.
Configurations 21 through 25 were pre-sterile, while configurations
26 through 30 were sterile. The cumulative amount released (.mu.g)
as a function of time and the amount of release (.mu.g) per day as
a function of time are presented in FIGS. 14 through 17.
[0288] Results from day 14 to day 289 showed an average release of
1.01.+-.0.23, 1.76.+-.0.57, 1.73.+-.0.30, 3.0.+-.1.26, and
3.32.+-.1.06 .mu.g/day for configurations 21, 22, 23, 23, and 25,
respectively. Similarly, the data for configurations 26, 27, 28,
29, and 30, which were the sterile counterparts, showed an average
release of 0.48.+-.0.03, 0.85.+-.0.09, 0.82.+-.0.08, 1.19.+-.0.15,
and 1.97.+-.0.69 .mu.g/day, respectively, from day 14 through day
289. Configuration #26 (2 holes--250 .mu.m-1 mm apart) achieved an
average release of 0.5 .mu.g/day (e.g., 0.48.+-.0.03 4/day from day
14 through day 289) and a total release of 5.76%.+-.0.32% over 289
days or close to 91/2 months. Based on its release rate, it has a
life span of 13.75 years. In general, the non-sterile
configurations are approximately twice as fast as the sterile
counterparts.
Example 4
Manufacture and In Vivo Testing of Intraocular Implants Containing
Fluocinolone and a Polymer Coating
[0289] An in vivo study was conducted with an implant as shown by
configuration #29 in Example 3. The implant was manufactured as
described in Example 3. Configuration #29 achieved an average
release of 1.19.+-.0.15 .mu.g/day, and a total release of
14.28%.+-.1.59% over 289 days when tested in vitro.
[0290] The in vivo study was conducted on four rabbits. The
fluocinolone-containing implants were surgically implanted into the
posterior segment (i.e., the vitreous) of the right eye (OD) and
left eye (OS) of each rabbit. The aqueous humor (15-20 .mu.L) and
the vitreous humor (150-200 .mu.L) were withdrawn for the first two
rabbits, while the sampling for the remaining two rabbits was
determined by a sampling schedule wherein the sampling days were
days 7, 14, 21, 40, and 60, 90, and 120. The results of the in vivo
study are shown in Table 4.
TABLE-US-00004 TABLE 4 Fluocinolone acetonide Levels in Vitreous
Humor of Rabbit Eyes Fluocinolone (ng/mL) Posterior Day Segment 7
14 21 40 60 90 120 8408D 242.00 8408S 88.60 8399D 9.08 6.84 3.06
4.56 10.26 15.18 8399S 44.00 74.20 85.80 83.60 75.60 44.00 8407D
105.80 87.20 135.80 68.60 57.20 8407S 16.64 6.78 14.92 6.62 3.46
8397D 44.00 42.20 32.40 24.20 8397S 40.80 22.60 23.00 24.80 Average
95.92 50.87 45.71 42.40 50.61 36.08 28.14 SD 102.68 47.16 47.13
2.26 50.19 29.46 19.49
[0291] The mean vitreous levels of fluocinolone were relatively
higher in the first week and then remained at approximately between
30 and 50 ng/mL beyond the second week. Fluocinolone acetonide was
not detected at any time point in the anterior chamber of all
eyes.
[0292] Thus, by way of Examples 3 and 4, implants have been
developed that can deliver fluocinolone at a substantially constant
release rate of 2 .mu.g/day or 0.5 .mu.g/day for extended periods
of time (e.g., for over 1-2 years).
[0293] Configuration #29 (2 hole--500 .mu.m-1 mm) was used in the
in vivo study and fluocinolone acetonide concentrations were
measured between 0.026 .mu.g/mL to 0.096 .mu.g/mL over 120 days in
the vitreous, while essentially no level was found in the aqueous
humor.
[0294] It was noticed that the release profiles differed depending
on when the implants were sterilized. For some configurations, the
before sterilization release rates are about twice as fast as the
after sterilization ones, and in other configurations, the reverse
was observed. It is possible that sterilization may change the size
of the holes in the implants. Two animals developed cataracts after
day 120.
Example 5
Treatment of Uveitis with an Intraocular Implant Containing
Fluocinolone Associated with a Biodegradable Polymer Matrix
[0295] A 48 year old female presents with posterior uveitis. She
complains of sensitivity to light and ocular pain. An implant
containing 250 .mu.g of fluocinolone acetonide and 250 .mu.g of a
combination of biodegradable polymers (R502H and R202H at a 1:2
ratio, as described above in Example 1) is placed in the vitreous
of both of the woman's eyes using a trocar. After about 2 days, the
woman begins to notice a decrease in ocular pain and light
sensitivity. She also notices a decreased blurring of vision, and a
decrease in floaters. Substantial relief from the uveitis symptoms
is obtained within about 7 days, and persists for about three
months.
Example 6
Treatment of Uveitis with an Intraocular Implant Containing
Fluocinolone Associated with a Polymeric Coating
[0296] A 62 year old male presents with posterior uveitis. An
implant containing 250 .mu.g of fluocinolone acetonide with a
polymeric coating having two 500 .mu.m diameter holes spaced 1 mm
apart is implanted into the vitreous of both of the patient's eyes
using a trocar. The patient reports a decrease in pain and
improvement in vision within a week after implantation. The
improvements persist for about two years. No cataracts develop over
that time.
Example 7
Treatment of Macular Edema with a Steroid Containing Intraocular
Implant
[0297] A 53 year old male with macular edema is treated by
injecting a biodegradable implant into the vitreous of each of the
patient's eyes using a syringe with a needle. The implants contain
500 .mu.g of fluocinolone acetonide and 500 .mu.g of PLGA. The
patient reports a decrease in pain and improvement in vision within
a week after implantation. The improvements persist for about two
years. No cataracts develop over that time.
Example 8
[0298] Treatment of macular degeneration with a steroid containing
intraocular implant.
[0299] A 82 year old female diagnosed with macular degeneration in
her right eye is treated by intravitreal placement of a
biodegradable implant containing 600 .mu.g of fluocinolone
acetonide and 500 .mu.g of PLGA. The implant is placed near the
fovea without interfering with the patient's vision. Further
ophthalmic diagnosis indicates that macular degeneration is
suspended, and the patient does not perceive further vision loss
associated with macular degeneration. Throughout the treatment,
intraocular pressure remains within acceptable limits.
Example 9
Effects of Polymer Properties and Drug Load on Intraocular
Implants
[0300] This example describes effects of poly(lactide-co-glycolide)
(PLGA) polymer properties and drug load on in-vitro drug release
profiles of steroids from polymeric implants. More specifically,
this example describes the effects of polymer molecular weight
(MW), lactide-glycolide (LG) ratio, and steroid load on the release
profile of triamcinalone acetonide (TA) or beclomethasone
dipropionate (BD) from poly(D, L-lactide-co-glycolide) polymer
implants containing triamcinalone acetonide (TA) or beclomethasone
dipropionate (BD).
[0301] Drug release profiles of the present implants are related to
the molecular weight (MW) of the polymer, such as PLGA in this
example, the lactide-glycolide ratio (LG) of the polymer, and the
drug load or amount of drug in the implant. Steroid release from
the implants was examined in phosphate buffered saline (pH 7.4;
PBS) or citrate phosphate buffer containing 0.1%
cetytrimethylammonium bromide (pH 5.4; CTAB).
[0302] In short, the implants were made by melt extrusion, and the
steroid release from the implant was assayed by HPLC after
incubation at 37.degree. C. in phosphate buffered saline pH 7.4 or
citrate phosphate buffer with 0.1% cetyltrimethylammonium bromide
pH 5.4. Triamcinalone release from the implants was monitored for
90 days, and beclomethasone dipropionate release from implants was
monitored for 35 days.
[0303] The results of these experiments show that both steroids
release much faster in the citrate buffer compared to the phosphate
buffer. During the first 30 days, the release profiles of the two
steroids are very similar even though triamcinalone acetonide is
about 150 times more water soluble than beclomethasone
dipropionate. Polymer properties have a minor effect on the release
profile in this time frame or portion of the release profile (e.g.,
within approximately the first 30 days). In this early phase, the
release appears to be controlled by the drug dissolution. The
polymer properties become more important after the first 30 days or
during a second time frame or portion of the release profile as the
polymer's hydrolysis rate differences become more important.
[0304] Triamcinalone acetonide was obtained from Pharmacia Upjohn
Co. Beclamethasone dipropionate was obtained from Sigma. PLGA
polymers RG502, RG504, RG752, and RG755 were obtained from
Boehringer-Ingelheim Pharma GmbH & Co. (Germany). Saline
solution (0.9% NaCl) was obtained from VWR Scientific.
Cetyltrimethylammonium bromide (CTAB) was obtained from
Aldrich.
[0305] The following equipment was used: a ball mill (model mm200;
F. Kurt Retsch GmbH & Co., Germany); a turbula shaker (model
T2F Nr.990720, Glen Mills, Inc., New Jersey); a piston extruder
obtained from APS Engineering, Inc.; a compactor (model A-1024,
Jamesville Tool & Manufacturing, Inc., Milton Wis.); a shaking
water bath (model 50, Precision Scientific, Winchester, Va.); a
high pressure liquid chromatograph (HPLC, model Alliance 2695,
Equipped with a Waters 2497 Dual Wavelength Absorbance Detector,
Waters, Inc., Milford, Mass.); and an oven (model 1330F, VWR
Scientific, Cornelius, Oreg.).
[0306] In this example, implants were produced by an extrusion
process. Steroids and polymer(s) were combined in a stainless steel
ball-mill capsule along with two stainless steel mixing balls. The
capsule was placed on the ball mill for five minutes at 20 cps. The
capsule was removed from the ball mill and the content was stirred
with a spatula; then placed back on the ball mill. This was
repeated for two more five-minute cycles. The ball-mill capsule was
then placed on a Turbula mixer for five minutes at 20 cps. The
content of the capsule was transferred in small increments to an
extruder barrel fitted with a die using a spatula and a small
stainless steel funnel. After each increment, the powder was
compacted in the extruder barrel with the compactor set at 50 psi.
When the extruder barrel was full, it is transferred to the
extruder and the extruder was heated to temperature and allowed to
equilibrate. The polymer steroid mixture was extruded through the
die at 0.025 in/min.; the resulting filament was cut into
approximately four-inch lengths and placed into a 60-mL screw cap
vial, which was placed in a laminated foil pouch with a desiccant
pack.
[0307] The experimental conditions for the extrusions are shown in
Table 5 and Table 6 for triamcinalone acetonide and beclamethasone
dipropionate, respectively.
TABLE-US-00005 TABLE 5 Triamcinalone Acetonide/PLGA Extrusion
Parameters Poly- Extru- Extru- mer Drug Compactor Diameter sion
sion Poly- ratio, Load, Press, of Die, Speed, Temp, mer % % psi um
''/min .degree. C. RG752 100 30 50 720 0.0025 95 RG752 100 50 50
720 0.0025 96 RG755 100 30 50 720 0.0025 97 RG755 100 50 50 720
0.0025 96 RG502 100 30 50 720 0.0025 97 RG502 100 50 50 720 0.0025
98 RG504 100 30 50 720 0.0025 94 RG504 100 50 50 720 0.0025 98
RG755 100 50 50 720 0.0025 101 RG752 100 30 50 720 0.0025 87
TABLE-US-00006 TABLE 6 Beclomethasone/PLGA Extrusion Parameters
Poly- Extru- Extru- mer Drug Compactor Diameter sion sion Poly-
ratio, Loading, Press, of Die, Speed, Temp*, mer % % psi um ''/min
.degree. C. RG755 100 30 50 720 0.0025 94 RG755 100 50 50 720
0.0025 99-109 RG752 100 30 50 720 0.0025 95-100 RG752 100 50 50 720
0.0025 96 RG504 100 30 50 720 0.0025 98 RG504 100 50 50 720 0.0025
104-114 RG502 100 30 50 720 0.0025 89-99 RG502 100 50 50 720 0.0025
95-96 RG755 100 50 50 720 0.0025 95 RG752 100 30 50 720 0.0025 95
*The mixture of API (the active pharmaceutical ingredient, that is
the drug used) and polymer were left in the extruder at 90.degree.
C. for 10 min before extrusion was started.
[0308] The extruded filaments were cut into 1-mg weight rod-shaped
implants (rods). Each rod was placed in a 60-mL vial with 50 mL of
phosphate buffered saline pH 7.4 or citrate phosphate buffer pH 5.4
with 0.1% cetyltrimethylammonium bromide (CTAB) in an oscillating
water bath (50 rpm) at 37.degree. C. At each time point, the
released steroid was assayed (n=6) by HPLC, and the solution was
removed from the vial and replaced with fresh buffer. The steroid
release was measured after the following days: 1, 4, 7, 14, 21, 28,
35, 48 69, 77, and 90.
[0309] Triamcinalone acetonide (TA) released from the PLGA
(poly(lactide-co-glycolide) polymer implant was assayed by HPLC
(Waters, Milford, Mass.) employing a Waters Symmetry C18,
4.6.times.75 mm, 3 .mu.m column. The mobile phase was
acetonitrile-water (35:65, v/v) with a flow rate of 1.0 mL/min and
an injection volume of 20 .mu.L. Ultraviolet detection of TA was
done at 243 nm. The total run time was 10 min and the TA retention
time was 4.0 min. Quantization was based on peak area and a
triamcinalone acetonide standardization curve.
[0310] Beclomethasone dipropionate (BD) released from the PLGA
polymer implant was assayed by HPLC (Waters, Milford, Mass.)
employing a Discovery HS F5 C18, 4.6.times.150 mm, 5 .mu.m column.
The mobile phase was acetonitrile-water (85:15), v/v) with a flow
rate of 0.8 mL/min and an injection volume of 30 .mu.L. Ultraviolet
detection of BD was done at 240 nm. The total run time was 5 min
and BD retention time was 2.5 min. Quantization was based on peak
area and a BD standardization curve.
[0311] The results from the design were analyzed qualitatively at
three times during the dissolution--early, middle and late.
[0312] The triamcinalone acetonide release results are shown in
Tables 7-10 and in FIGS. 18 to 21, respectively.
[0313] As shown, TA released into the CTAB buffer faster than it
was released into the PBS buffer. Drug release rate can also be
effected by pH and surfactant which can alter the polymer's
hydrolysis rate and therefore the drug release rate.
[0314] The drug load in the polymer has the largest positive effect
on the drug release rate compared to MW and LG ratio for the first
30 days. After the first 30 days, the LG ratio dominated the drug
release rate and showed a negative effect. In other words, a higher
LG ratio resulted in a slower drug release. Without wishing to be
bound by any particular theory or mechanism of action, these
effects may be related to high drug loading early in the
dissolution resulting in more available drug at the polymeric
implant's surface. As drug becomes less available, the drug release
rate may be controlled by the hydrolysis of the polymer, which is
faster for the lower LG ratio polymer.
[0315] Molecular weight of the polymer had a positive effect on
drug release rate especially later in the dissolution--faster
release was observed with higher MW polymers. While not wishing to
be bound by any particular theory or mechanism of action, this may
occur because the lower MW polymer pack more densely, and the
higher MW polymer hydrolyze faster. Overall, the data show that
early drug release is controlled by the drug load but the later in
time drug release rate is controlled by the polymer hydrolysis
rate.
TABLE-US-00007 TABLE 7 Triamcinalone Release Results in Phosphate
Buffered Saline pH 7.4 for 30% Drug Load 755-30 752-30 504-30
502-30 752-30R Total release (%) 1 1.08 0.81 1.75 0.74 0.46 4 1.40
1.02 2.13 0.94 0.49 7 1.56 1.08 2.29 1.00 0.59 14 1.70 1.10 2.47
1.11 0.60 21 1.92 1.28 2.86 1.47 0.69 28 2.05 1.37 4.14 2.77 0.97
35 2.08 1.41 9.73 4.60 1.06 48 2.22 1.98 13.74 7.73 1.65 69 14.03
4.42 21.70 11.70 3.98 90 20.94 7.82 36.46 21.22 7.05 Standard
Deviation 1 0.08 0.12 0.14 0.04 0.09 4 0.05 0.11 0.13 0.04 0.03 7
0.04 0.04 0.06 0.04 0.03 14 0.03 0.02 0.07 0.05 0.02 21 0.03 0.03
0.03 0.01 0.04 28 0.05 0.03 0.19 0.02 0.11 35 0.02 0.03 1.09 0.09
0.05 48 0.12 0.03 0.83 0.33 0.10 69 1.87 0.06 2.09 0.73 0.25 90
0.34 0.94 3.05 3.10 0.53
TABLE-US-00008 TABLE 8 Triamcinalone Release Results in Phosphate
Buffered Saline pH 7.4 for 50% Drug Load 755-50 752-50 504-50
502-50 755-50R Total release (%) 1 1.83 2.01 1.88 1.97 2.20 4 2.93
2.32 2.56 2.57 3.75 7 3.68 2.44 2.74 2.84 4.62 14 4.66 2.58 2.93
3.09 5.68 21 5.23 2.73 3.16 3.46 6.21 28 5.60 2.87 4.29 4.23 6.62
35 5.75 2.98 6.37 4.92 6.84 48 5.92 3.70 8.07 7.44 7.04 69 7.69
5.35 14.47 10.79 7.84 90 9.42 7.38 39.38 33.66 8.59 Standard
Deviation 1 0.35 0.15 0.72 0.09 0.16 4 0.09 0.05 0.32 0.08 0.14 7
0.15 0.05 0.10 0.04 0.16 14 0.12 0.06 0.08 0.05 0.11 21 0.09 0.03
0.09 0.03 0.04 28 0.05 0.06 0.56 0.08 0.05 35 0.01 0.05 1.01 0.04
0.03 48 0.04 0.09 1.58 2.65 0.03 69 0.79 0.25 3.75 2.60 0.08 90
0.47 0.37 2.45 3.63 0.08
TABLE-US-00009 TABLE 9 Triamcinalone Release Results in Citrate
Phosphate Buffer pH 5.4 for 30% Drug Load 755-30 752-30 504-30
502-30 752-30R Total release (%) 1 1.79 1.93 2.50 1.07 0.69 4 2.18
1.93 2.85 1.12 0.74 7 2.35 2.22 3.03 1.13 0.86 14 2.61 3.05 3.23
1.21 0.94 21 3.00 4.62 4.73 1.59 0.96 28 3.45 12.44 16.60 7.99 1.00
35 3.57 12.59 45.16 25.70 1.00 48 4.05 12.99 94.39 77.56 1.46 69
18.96 42.24 95.24 83.21 45.40 77 58.09 83.17 63.83 90 92.97 96.82
79.93 Standard Deviation 1 0.19 1.11 0.12 0.05 0.05 4 0.03 0.00
0.02 0.04 0.03 7 0.06 0.26 0.04 0.02 0.01 14 0.05 1.18 0.02 0.03
0.03 21 0.21 2.06 0.04 0.02 0.02 28 0.27 3.92 0.27 0.64 0.03 35
0.07 0.06 2.99 2.69 0.00 48 0.27 0.04 3.90 2.92 0.04 69 0.48 3.20
0.50 3.24 2.29 77 2.48 6.49 2.71 90 3.88 5.73 4.08
TABLE-US-00010 TABLE 10 Triamcinalone Release Results in Citrate
Phosphate Buffer pH 5.4 for 50% Drug Load 755-50 752-50 504-50
502-50 755-50R Total release (%) 1 4.32 3.14 4.10 3.10 5.63 4 7.96
3.38 5.77 4.08 9.39 7 13.26 3.46 6.24 4.42 11.52 14 16.75 3.60 6.79
4.77 14.79 21 19.60 3.80 10.34 5.25 16.43 28 21.91 3.90 20.94 9.17
17.21 35 23.75 4.02 41.21 16.58 17.59 48 24.50 5.02 82.11 71.13
18.38 69 43.48 33.38 91.91 85.27 27.09 77 58.17 54.68 35.62 90
85.58 75.87 54.43 Standard Deviation 1 1.01 0.63 0.14 0.14 1.76 4
0.76 0.09 0.36 0.08 0.09 7 5.93 0.05 0.17 0.03 0.07 14 1.16 0.03
0.13 0.03 0.15 21 1.23 0.03 0.32 0.03 0.12 28 2.78 0.02 0.14 0.55
0.11 35 2.20 0.03 1.66 3.08 0.06 48 0.34 0.19 3.58 13.62 0.10 69
8.47 7.52 4.47 1.67 1.65 77 1.78 7.97 1.13 90 5.86 11.33 4.57
[0316] The beclomethasone dipropionate release results are shown in
Tables 11-14 and are plotted in FIGS. 22 to 25, respectively.
[0317] In these experiments, beclomethasone dipropionate release
was examined for about one month. In this early timeframe (e.g.,
within about 1 month), the release profiles for BD and TA were
similar even though BD is about 150 times less soluble than TA.
Changing to an acidic media increased the amount of released BD
slightly but not as much as the same medium change did for TA. The
BD release did not increase with increase drug load in the
phosphate buffer, but did in the CTAB buffer. The response to
increasing LG ratio was the same for both steroids for the first
month. The effect is relatively small in the first 30 days but
increasing the LG ratio decreases the amount of drug released. The
effect of MW was different for the two steroids; triamcinalone's
release increased slightly with higher MW in both media, whereas
beclomethasone's release decreased in PBS and increased in CTAB
with increasing MW.
TABLE-US-00011 TABLE 11 Beclomethasone Dipropionate Release Results
in Phosphate Buffered Saline pH 7.4 for 30% Drug Load 755-30 752-30
504-30 502-30 752-30R Total release (%) 1 0.31 0.34 1.23 1.46 0.72
4 1.86 3.07 2.90 2.75 2.27 7 2.64 3.74 3.64 3.52 3.22 14 3.03 4.36
4.12 3.95 3.58 21 3.56 4.92 4.80 4.61 4.13 28 4.11 5.32 6.09 5.53
4.62 35 4.45 5.80 6.82 6.68 5.03 48 69 90 Standard Deviation 1 0.05
0.41 0.35 0.06 0.19 4 0.57 0.28 0.48 0.34 0.22 7 0.12 0.43 0.28
0.26 0.22 14 0.17 0.09 0.16 0.21 0.28 21 0.27 0.18 0.18 0.08 0.11
28 0.14 0.44 0.51 0.16 0.12 35 0.16 0.16 0.13 0.11 0.15 48 69
90
TABLE-US-00012 TABLE 12 Beclomethasone Dipropionate Release Results
in Phosphate Buffered Saline pH 7.4 for 50% Drug Load 755-50 752-50
504-50 502-50 755-50R Total release (%) 1 0.11 0.18 0.70 1.01 0.75
4 0.78 1.95 2.22 2.00 1.84 7 1.13 2.78 2.57 2.50 2.34 14 1.29 3.19
2.91 2.75 2.72 21 1.62 3.68 3.25 3.21 3.20 28 1.88 4.15 3.87 3.72
3.56 35 2.02 4.42 4.22 4.36 3.75 48 69 90 Standard Deviation 1 0.07
0.09 0.24 0.30 0.07 4 0.37 0.19 0.16 0.14 0.17 7 0.12 0.10 0.30
0.18 0.16 14 0.04 0.09 0.08 0.08 0.08 21 0.09 0.08 0.20 0.10 0.04
28 0.15 0.11 0.12 0.16 0.08 35 0.08 0.17 0.15 0.19 0.03 48 69
90
TABLE-US-00013 TABLE 13 Beclomethasone Dipropionate Release Results
in Citrate Phosphate Buffer pH 5.4 for 30% Drug Load 755-30 752-30
504-30 502-30 752-30R Total release (%) 1 0.28 1.20 2.16 1.28 1.37
4 1.44 1.54 3.16 1.59 1.50 7 2.15 1.87 3.90 2.04 1.93 14 2.62 2.06
4.53 2.39 2.27 21 3.05 2.35 7.45 3.68 2.54 28 3.32 2.50 12.51 7.09
2.82 Standard Deviation 1 0.16 0.22 0.23 0.25 0.10 4 0.24 0.11 0.22
0.16 0.11 7 0.15 0.09 0.17 0.03 0.08 14 0.09 0.21 0.08 0.11 0.06 21
0.09 0.05 0.24 0.16 0.16 28 0.10 0.22 0.74 0.29 0.07
TABLE-US-00014 TABLE 14 Beclomethasone Dipropionate Release Results
in Citrate Phosphate Buffer pH 5.4 for 50% Drug Load 755-50 752-50
504-50 502-50 755-50R Total release (%) 1 2.01 0.47 3.07 2.16 3.80
4 6.26 1.77 6.01 3.16 7.64 7 9.00 2.55 7.48 3.98 10.30 14 12.40
3.51 8.45 4.73 13.49 21 14.16 4.06 10.59 6.04 15.06 28 15.07 4.44
15.31 9.21 15.95 Standard Deviation 1 0.36 0.06 0.74 0.37 0.42 4
0.63 0.24 0.51 0.27 0.61 7 0.54 0.18 0.17 0.16 0.58 14 0.49 0.66
0.15 0.18 0.65 21 0.26 0.15 0.28 0.12 0.22 28 0.13 0.12 0.79 0.29
0.08
[0318] Based on these results, the release of low water soluble
steroids from PLGA implants is primarily limited by the dissolution
of the steroid in the first thirty days, and not the loading or
amount of the steroid, or the polymer matrix properties. In the
early part of the dissolution (e.g., during the first portion of
the drug release profile), the release rates of the two steroids
are very similar even though their solubilities are quite
different. During this period the drug release rate appears to be
controlled by the steroid dissolution with the polymer properties
having a minor effect. Later in the dissolution (e.g., during a
second portion of the drug release profile), the steroid release is
more dependent on polymer properties as the hydrolysis rates of the
polymers become more important. Changing to a lower pH media with a
lower surface tension increases the amount released for both
steroids.
Example 10
Treatment of Uveitis with an Intraocular Implant Comprising
Fluocinolone and Timolol
[0319] Although the patient of Example 5 experiences relief from
the symptoms of uvetitis with the implant containing fluocinololone
acetonide, the intraocular pressure in the eye of the patient
increases with time.
[0320] An implant containing 250 .mu.g of fluocinolone acetonide,
250 .mu.g of a combination of biodegradable polymers (R502H and
R202H in a 1:2 ratio) and 500 .mu.g of timolol, an antiglaucoma
drug, is substituted for the implant of Example 5 that contains
fluocinololone acetonide without an antiglaucoma drug. The patient
experiences relief from the symptoms of uvetitis, and the
intraocular pressure of the patient remains within acceptable
limits. The implant comprising a steroid and an antiglaucoma drug,
timolol, provides relief from the symptoms of uvetitis while
maintaining acceptable intraocular pressure over extended periods
of time.
Example 11
Treatment of Macular Edema with a First Intraocular Implant
Comprising Fluocinolone and a Second Intraocular Implant Comprising
Timolol
[0321] Although the patient of Example 7 experiences a decrease in
pain and improvement in vision after implantation of the implant
containing fluocinolone acetonide and PLGA, the intraocular
pressure in the eye of the patient increases over time.
[0322] A second implant containing 1 mg of timolol and 250 .mu.g of
combination of biodegradable polymers (R502H and R202H in a 1:2
ratio) is implanted in the eye of the patient. The intraocular
pressure of the patient decreases, and the patient continues to
have improvement in vision and decrease in pain.
Example 12
Treatment of Uveitis with an Intraocular Implant Comprising
Alternating Layers of Fluocinolone and Timolol
[0323] A 56 year old male presents with posterior uveitis. An
implant containing alternating layers of flucinololone acetonide
and brimonidine is formed, where the implant contains a total of
250 .mu.g of flucinololone associated with 250 .mu.g of a
combination of biodegradable polymers (R502H and R202H in a 1:2
ratio) and 500 .mu.g of timolol associated with 500 .mu.g of
PLGA.
[0324] The implant is injected into the vitreous of each of the
patient's eyes using a syringe with a needle. The patient reports
improvement in vision, and the intraocular pressure remains within
acceptable limits.
Example 13
Treatment of Anterior Uveitis with an Intraocular Implant
Comprising Dexamethasone and a Second Implant Comprising
Timolol
[0325] Uveitis, a term originally coined to describe inflammation
of the uveal tract (iris, ciliary body, choroid, the middle layer
of the eye), comprises a group of diverse disease affecting not
only the uvea, but also the retinal, optic nerve and vitreous. The
current International Uveitits Study Group classification separates
uveitis by anatomical location of the disease according to the
major visible signs. One of the most common forms of uveitis is
anterior uveitis, which affects the area of the iris (irititis),
cilary body (cyclitis) and aqueous humor. Uveitis can also be
classified by its duration as acute or chronic (more than three
months in duration) and recurrent. The causes of uveitis are
diverse and include infection (viral, parasitic, fungal and
bacterial), traumatic injury to the eye, and systemic or local
autoimmune diseases, although most cases are idiopathic.
[0326] Although the topical administration of steroids is the
current mainstay of therapy for anterior uveitis, a periocular
injection of steroids may also be added in the patient is not
responding adequately or in the disease is severe. Additionally,
oral corticosteroids may be given if topical administration is
ineffective.
[0327] Adverse effects from topical steroid use include elevated
10P, optic nerve damage, and cataract formation or progression.
Additional risks from periocular injection include globe rupture,
fibrosis of the extraocular muscles, and ptosis (eyelid droop) with
repeated injections. Systemic absorption from depot periocular
administration does occur as well. Side effects of systemic steroid
treatment include hypertension, hyperglycemia, gastrointestinal
hemorrhage, osteoporosis, and psychosis.
[0328] A 52 year old female presents with persistent,
non-infectious posterior uveitis in the right eye. Following
diagnosis, the patient is given ophthalmic gatifloxacin at an
antibacterial concentration, and told to instill a drop on the
right eye 4 times a day (QID) for 3 days. On the third day, the
patient is administered a first biodegradable polymeric implant
containing 700 .mu.g of micronized dexamethasone in a 60:40 weight
ration of drug to polymer. The polymer portion of the implant
comprises a combination of biodegradable polymers (R502H and R202H
in a 1:2 ratio).
[0329] At the same time, the patient is also co-administered a
first biodegradable polymeric implant containing 700 .mu.g of
micronized brimonidine tartrate in a 60:40 weight ration of drug to
polymer (R502H and R202H in a 1:2 ratio). The second biodegradable
polymeric implant is associated with a polymer coating that is
impermeable to the vitreous and containing a plurality of holes,
drilled through the polymer coating with a laser, to allow the
brimonidine to permeate into the vitreous.
[0330] Both implants are simultaneously injected into the eye of
the female patient by intracameral injection through the pars plana
using an applicator system comprising a 22 gauge needle.
[0331] The patient is then monitored weekly for six weeks following
implantation of the dexamethasone and brimonidine implants. At each
monitoring visit the patient's right eye is carefully examined for
signs or abnormalities; the features observed include the eyelid,
conjunctiva, cornea, anterior chamber, iris color, lens status,
vitreous cells, and retina, including macula, and the optic nerve.
The patient's intraocular pressure is also monitored.
[0332] At the end of the six week period, the patient has improved
vision compared to her situation prior to the insertion of the
implants, and the inflammation associated with the uveal tract is
absent. The intraocular pressure in the eye of the patient remains
within normal levels; no significant increase in degeneration of
the retina or optic nerve is seen during the treatment regimen.
Example 14
Treatment of Anterior Uveitis with an Intraocular Implant
Comprising Alternating Layers of Dexamethasone and Timolol
[0333] Intermediate uveitis is characterized by inflammation of the
middle of the eye, including the vitreous and peripheral retina.
Pars planitis is considered a subset of intermediate uveitis and is
characterized by the presence of "snowbanking" over the pars plana
and ora serrata. Some ophthalmologists believe that patients with
pars planitis have a more severe disease, for example with more
macular edema, than other patients with intermediate uveitis.
[0334] Vision loss associated with intermediate uveitis is usually
due to cystoid macular edema, inflammatory vitreal haze and debris,
and cataract. The former two conditions are usually responsive to
treatment with anti-inflammatory agents, including
anti-inflammatory steroids.
[0335] A 56 year old male presents with intermediate uveitis in
both eyes, in each case showing involvement of the vitreous
(vitreal haze). Following diagnosis, the patient is given
ophthalmic gatifloxacin at an antibacterial concentration, and told
to instill a drop on the right eye 4 times a day (QID) for 3 days.
On the third day, the patient is administered a biodegradable
polymeric implant containing 500 .mu.g of micronized dexamethasone
and 500 .mu.g brimonidine in a 60:40 weight ration of drug to
polymer, and comprising interleaved alternative layers of drug. The
polymer portion of the implant comprises a combination of
biodegradable polymers (R502H and R202H in a 1:2 ratio).
[0336] The implant is injected through the pars plana into the
vitreous of each of the patient's eyes using an applicator with a
22 gauge needle. The patient is monitored weekly for six weeks
following administration of the implant. The primary indication of
efficacy is clearing of vitreal haze, giving rise to increased
visual acuity.
[0337] At the end of the six-week monitoring period the patient
reports improvement in vision, and tests an improvement of 3 lines
in visual acuity. Observation shows no trace of vitreal haze
remaining, and the intraocular pressure remains within acceptable
limits.
[0338] The present invention also encompasses the use of any and
all possible combinations of the therapeutic agents disclosed
herein in the manufacture of a medicament, such as a drug delivery
system or composition comprising such a drug delivery system, to
treat one or more ocular conditions, including those identified
above.
[0339] All references, articles, publications and patents and
patent applications cited herein are incorporated by reference in
their entireties.
[0340] While this invention has been described with respect to
various specific examples and embodiments, it is to be understood
that the invention is not limited thereto and that it can be
variously practiced within the scope of the following claims.
* * * * *
References